Heterocyclyl Derivatives and their use as Prostaglandin D2 Receptor Modulators

ABSTRACT

The present invention relates to phenyl-substituted heterocyclyl derivatives of the formula (I), 
     
       
         
         
             
             
         
       
     
     wherein Z, n, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2  receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

FIELD OF THE INVENTION

The present invention relates to heterocyclyl derivatives of formula (I) and their use as prostaglandin receptor modulators, most particularly as prostaglandin D₂ receptor (“DP receptor”) modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation. In particular, such derivatives may be used alone or in pharmaceutical compositions for the treatment of both, chronic and acute allergic/immune diseases/disorders such as asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.

BACKGROUND OF THE INVENTION

As a response to allergen exposure in allergic conditions, mast cells are activated and release mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D₂ (PGD₂). These mediators interact with their respective receptors and cause physiological effects such as increased vascular permeability, edema, pruritus, nasal and pulmonary congestion, bronchoconstriction, and mucus secretion. An increased vascular permeability for example, allows excessive infiltration of eosinophilic and basophilic leukocytes into the tissue and thus amplifies the allergic response. Current treatments of allergic diseases comprise agents that can block or otherwise interrupt such interactions, e.g. anti-histamines (histamine H1 receptor antagonists), leukotriene receptor antagonists, beta-adrenergic receptor agonists, and corticosteroids. Generally, treatments with anti-histamines and leukotriene antagonists are limited in efficacy, and long-term usage of corticosteroids is often associated with unwanted side effects.

PGD₂ is an agonist known to act on two G-protein-coupled receptors, the PGD₂ receptor DP1 and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as “DP2 receptor”).

Elevated PGD₂ levels are considered to cause inflammation as observed in allergic diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic dermatitis and the like. Therefore, blocking the interaction of PGD₂ with its receptors is considered a useful therapeutic strategy for the treatment of such diseases.

GB 2388540 discloses the use of ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)-1,2,3,4-tetrahydrocarbazole-9-propionic acid), a TxA2 receptor (also referred to as “TP receptor”) antagonist with additional antagonistic activity on CRTH2, for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjunctivitis. In T. Ishizuka et al., Cardiovascular Drug Rev. 2004, 22(2), 71-90 effects of ramatroban on late-phase inflammation are described. Furthermore, oral bioavailability of ramatroban and its ability to inhibit prostaglandin D₂-induced eosinophil migration in vitro has been reported (Journal of Pharmacology and Experimental Therapeutics, 305(1), p. 347-352 (2003)). A different CRTH2 receptor antagonist has been recently described to have positive clinical effects in the treatment of allergic rhinoconjunctivitis (F. Horak et al., Allergy, 2012, 67(12), 1572-9) and asthma (N. Barnes et al., Clin. Exp. Allergy, 2012, 42(1), 38-48).

CRTH2 receptor antagonists containing a biphenyl-acetic acid moiety have been for instance described in WO 2009/099901, WO 2009/099902, WO 2009/108720, WO 2010/042652 and WO 2011/017201. Biphenyloxy-acetic acid derivatives as CRTH2 receptor antagonists have been disclosed in WO 2009/089192. Phenyl-substituted heterocyclyl derivatives have been described in WO 2012/004722.

DESCRIPTION OF THE INVENTION

1) The present invention relates to phenyl-substituted heterocyclyl derivatives of the formula (I),

wherein

R¹ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)alkylsulfonyl, halogen or cyano;

R² represents hydrogen or halogen;

one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkyl, carboxy-cyclopropyl or carboxy-(C₁-C₃)alkoxy and the other two represent independently of each other hydrogen, (C₁-C₄)alkoxy or halogen;

R⁶ represents hydrogen, (C₁-C₄)alkoxy or halogen;

R⁷ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₃-C₆)cycloalkyl-methoxy, (C₃-C₆)cycloalkyloxy, methoxy-ethoxy, di-[(C₁-C₂)alkyl]-amino, (C₁-C₄)fluoroalkyl, (C₁-C₄)fluoroalkoxy, halogen or (C₁-C₄)alkylsulfonyl;

-   -   or R⁶ and R⁷ together represent methylendioxy or ethylendioxy;     -   R⁸ represents     -   (C₂-C₅)alkyl;     -   (C₁-C₅)alkyl which is mono- or di-substituted wherein the         substituents are independently selected from the group         consisting of hydroxy, (C₁-C₄)alkoxy, oxo, —NR⁹R¹⁰, optionally         substituted (C₃-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy, optionally         substituted heteroaryloxy or optionally substituted         aryl-(C₁-C₂)alkoxy;     -   (C₃-C₅)alkenyl;     -   (C₂-C₃)alkenyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl;     -   (C₃-C₅)alkynyl;     -   (C₃-C₆)cycloalkyl which is unsubstituted, mono-, di-, tri- or         tetra-substituted with methyl; mono-substituted with oxo;         mono-substituted with optionally substituted aryl; or         mono-substituted with optionally substituted heteroaryl; or     -   heterocyclyl which is optionally mono-substituted with oxo;

R⁹ represents (C₁-C₄)alkyl;

R¹⁰ represents optionally substituted diphenylmethyl;

n represents 1 or 2;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

The compounds of formula (I) according to embodiment 1) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the (Z)- or (E)-configuration unless indicated otherwise. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

Notably, the compounds of formula (I) may be present as atropisomers, i.e. they may have the conformation as depicted in formula (I_(St1)) or as depicted in formula (I_(St2)). Atropisomers may have a sufficiently high rotational barrier to be conformationally stable at a temperature around rt. In that case mixtures of atropisomers may be separated into single isomers. It is to be understood that formula (I) comprises mixtures of atropisomers (notably racemates) as well as separated atropisomers of formula (I_(St1)) and of formula (I_(St2)). In one embodiment compounds of formula (I) are either achiral or present as mixtures of atropisomers. In another embodiment compounds of formula (I) are either achiral or atropisomers of formula (I_(St1)). In still another embodiment compounds of formula (I) are either achiral or atropisomers of formula (I_(St2)).

In this patent application, variably attached bonds may be used for substituents or groups. In such case it is meant that the substituent or group is attached to either atom linked by the bond into which the variably attached bond is drawn into. For example, formula (I) encompasses the following two formulas:

The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention (except for the compounds of formula I_(P) which have their own definitions) and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

The term “alkyl”, used alone or in combination, refers to a straight or branched chain alkyl group containing one to five carbon atoms. The term “(C_(x)-C_(y))alkyl” (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C₁-C₅)alkyl group contains from one to five carbon atoms. Representative examples of (C₁-C₅)alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl and 2,2-dimethyl-prop-1-yl. The alkyl group may be unsubstituted or substituted as explicitly defined.

In case “R¹” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred is methyl.

In case “R⁷” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl, n-propyl and iso-propyl.

In case “R⁸” represents “(C₂-C₅)alkyl” the term means (C₂-C₅)alkyl groups as defined above. Examples of said groups are ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl and 2,2-dimethyl-prop-1-yl. Preferred are ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, 2-methyl-but-1-yl, 3-methyl-but-1-yl and 2,2-dimethyl-prop-1-yl.

In case “R⁸” represents mono- or di-substituted (C₁-C₅)alkyl the term “(C₁-C₅)alkyl” means (C₁-C₅)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl and 2,2-dimethyl-prop-1-yl. Preferred are methyl, ethyl, n-propyl, iso-propyl and iso-butyl.

In case “R⁹” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred is methyl.

In case “(C₁-C₄)alkyl” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred is methyl.

The term “carboxy-(C_(x)-C_(y))alkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one hydrogen atom has been replaced with —COOH. For example a carboxy-(C₁-C₃)alkyl group contains in the alkyl group from one to three carbon atoms in which one hydrogen atom has been replaced with —COOH. Representative examples of carboxy-(C₁-C₃)alkyl groups include carboxy-methyl, 1-carboxy-ethyl, 2-carboxy-ethyl, 1-carboxy-propyl, 2-carboxy-propyl and 3-carboxy-propyl. Preferred are carboxy-methyl and 1-carboxy-ethyl.

The term “(C_(x)-C_(y))fluoroalkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro. For example a (C₁-C₄)fluoroalkyl group contains from one to four carbon atoms in which one to nine hydrogen atoms have been replaced with fluoro.

In case “R¹” represents “(C₁-C₄)fluoroalkyl” the term means a (C₁-C₄)fluoroalkyl group as defined above. Representative examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

In case “R⁷” represents “(C₁-C₄)fluoroalkyl” the term means a (C₁-C₄)fluoroalkyl group as defined above. Representative examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

In case “(C₁-C₄)fluoroalkyl” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)fluoroalkyl” means (C₁-C₄)fluoroalkyl groups as defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

The term “(C_(x)-C_(y))alkenyl” (x and y each being an integer) refers to a straight or branched chain alkenyl group containing x to y carbon atoms. For example a (C₂-C₃)alkenyl group contains from two to three carbon atoms. Examples of (C₂-C₃)alkenyl groups include ethenyl and propenyl. Preferred is ethenyl. The (C₂-C₃)alkenyl group is substituted as explicitly defined. A (C₃-C₅)alkenyl group contains from three to five carbon atoms. Representative examples of (C₃-C₅)alkenyl groups include propenyl, butenyl and pentenyl. Preferred are 3-methyl-2-butenyl and 3-methyl-3-butenyl.

The term “(C_(x)-C_(y))alkynyl” (x and y each being an integer) refers to a straight or branched chain alkynyl group containing x to y carbon atoms. For example a (C₃-C₅)alkynyl group contains from three to five carbon atoms. Representative examples of (C₃-C₅)alkynyl groups include propynyl, butynyl and pentynyl. Preferred is 3-butynyl.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O— group wherein the alkyl group is as defined before. The term “(C_(x)-C_(y))alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkoxy group contains from one to four carbon atoms. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy.

In case “R¹” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R³” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁴” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁵” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁶” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁷” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred are methoxy, ethoxy, n-propoxy, iso-propoxy, iso-butoxy and tert-butoxy.

In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with (C₁-C₄)alkoxy” the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “(C₁-C₄)alkoxy” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

The term “aryl-(C₁-C₂)alkoxy” refers to an (C₁-C₂)alkoxy group as defined above in which one hydrogen atom has been replaced with an aryl group as defined below. Examples of aryl-(C₁-C₂)alkoxy groups are aryl-methoxy, 1-aryl-ethoxy and 2-aryl-ethoxy. Preferred is aryl-methoxy.

The term “carboxy-(C_(x)-C_(y))alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms in which one hydrogen atom has been replaced with —COOH. For example a carboxy-(C₁-C₃)alkoxy group contains in the alkoxy group from one to three carbon atoms in which one hydrogen atom has been replaced with —COOH. Representative examples of carboxy-(C₁-C₃)alkoxy groups include carboxy-methoxy, 1-carboxy-ethoxy, 2-carboxy-ethoxy, 1-carboxy-propoxy, 2-carboxy-propoxy and 3-carboxy-propoxy. Preferred is carboxy-methoxy.

The term “(C_(x)-C_(y))fluoroalkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro. For example a (C₁-C₄)fluoroalkoxy group contains from one to four carbon atoms in which one to nine hydrogen atoms have been replaced with fluoro.

In case “R⁷” represents “(C₁-C₄)fluoroalkoxy” the term means a (C₁-C₄)fluoroalkoxy group as defined above. Representative examples of said groups are difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.

In case “(C₁-C₄)fluoroalkoxy” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)fluoroalkoxy” means (C₁-C₄)fluoroalkoxy groups as defined above. Representative examples of said groups are difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred is trifluoromethoxy.

The term “alkylsulfonyl”, used alone or in combination, refers to an alkyl-S(O)₂— group wherein the alkyl group is as defined before, which is attached to the rest of the molecule via the sulfur-atom. The term “(C_(x)-C_(y))alkylsulfonyl” (x and y each being an integer) refers to an alkylsulfonyl group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkylsulfonyl group contains from one to four carbon atoms. Representative examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

In case “R¹” represents “(C₁-C₄)alkylsulfonyl” the term means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred is methylsulfonyl.

In case “R⁷” represents “(C₁-C₄)alkylsulfonyl” the term means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred is methylsulfonyl.

The term “di-[(C₁-C₂)alkyl]-amino” refers to an amino group which is substituted by two (C₁-C₂)alkyl groups as defined above, wherein the two (C₁-C₂)alkyl groups may be the same or different. Examples of di-[(C₁-C₂)alkyl]-amino groups include dimethylamino, methyl-ethyl-amino and diethylamino. Preferred is dimethylamino.

The term “halogen” means fluoro, chloro, bromo or iodo.

In case “R¹” represents “halogen” the term means fluoro, chloro or bromo; and preferably fluoro or chloro.

In case “R²” represents “halogen” the term means fluoro or chloro and preferably fluoro. In case “R³” represents “halogen” the term means fluoro or chloro and preferably fluoro.

In case “R⁴” represents “halogen” the term means fluoro or chloro and preferably chloro.

In case “R⁵” represents “halogen” the term means fluoro or chloro and preferably fluoro.

In case “R⁶” represents “halogen” the term means fluoro, chloro or bromo; and preferably fluoro or chloro.

In case “R⁷” represents “halogen” the term means fluoro, chloro or bromo; and preferably fluoro or chloro.

In case “halogen” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term means fluoro, chloro, bromo or iodo; and preferably fluoro or chloro.

The term “oxo” means an oxygen atom which is attached to a carbon atom via a double bond.

The term “cycloalkyl”, used alone or in combination, refers to a cycloalkyl group containing three to six carbon atoms. The term “(C_(x)-C_(y))cycloalkyl” (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C₃-C₆)cycloalkyl group contains from three to six carbon atoms. A cycloalkyl group containing four, five or six carbon atoms may optionally be annelated to a benzene or a pyridine ring, wherein the benzene ring is optionally mono-substituted with methoxy. Examples of (C₃-C₆)cycloalkyl groups are cyclopropyl, cyclobutyl, bicyclo[4.2.0]octa-1,3,5-trienyl, cyclopentyl, indanyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl. The cycloalkyl group may be unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with optionally substituted (C₃-C₆)cycloalkyl” the term “(C₃-C₆)cycloalkyl” means (C₃-C₆)cycloalkyl groups as defined above. Representative examples of said groups are cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl. Preferred are cyclopropyl, cyclopentyl, indanyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl and 5,6,7,8-tetrahydroquinolinyl. The (C₃-C₆)cycloalkyl groups are unsubstituted or mono-substituted with (C₁-C₄)alkyl; (C₁-C₄)alkoxy; hydroxy; or phenyl which is unsubstituted or mono-substituted with halogen (notably fluoro). Preferred examples of optionally substituted (C₃-C₆)cycloalkyl groups are cyclopropyl, 1-phenyl-cyclopropyl, 1-(2-fluoro-phenyl)-cyclopropyl, 1-(3-fluoro-phenyl)-cyclopropyl, 1-(4-fluoro-phenyl)-cyclopropyl, cyclopentyl, indan-1-yl, indan-2-yl, cyclohexyl, 1,2,3,4-tetrahydronaphth-1-yl, 1-methyl-1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl and 5,6,7,8-tetrahydroquinolin-8-yl.

In case “R⁸” represents “(C₃-C₆)cycloalkyl” the term means (C₃-C₆)cycloalkyl groups as defined above. Representative examples of said groups are cyclopropyl, cyclobutyl, bicyclo[4.2.0]octa-1,3,5-trienyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl which is in the aromatic part unsubstituted or mono-substituted with methoxy. Preferred is cyclopropyl. The (C₃-C₆)cycloalkyl groups may be unsubstituted or substituted as explicitly defined.

The term “carboxy-cyclopropyl” refers to a cyclopropyl group in which one hydrogen atom has been replaced with —COOH. Examples of carboxy-cyclopropyl groups include 1-carboxy-cyclopropyl and 2-carboxy-cyclopropyl. Preferred is 1-carboxy-cyclopropyl.

The term “(C₃-C₆)cycloalkyl-methoxy” refers to a methoxy group in which one hydrogen atom has been replaced with a (C₃-C₆)cycloalkyl group as defined before. Representative examples of (C₃-C₆)cycloalkyl-methoxy groups are cyclopropyl-methoxy, cyclobutyl-methoxy, cyclopentyl-methoxy and cyclohexyl-methoxy. Preferred is cyclopropyl-methoxy.

The term “(C₃-C₆)cycloalkyloxy” refers to a (C₃-C₆)cycloalkyl-O— group wherein the (C₃-C₆)cycloalkyl group is as defined before. Examples of (C₃-C₆)cycloalkyloxy groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. Preferred is cyclopropyloxy.

The term “aryl”, used alone or in any combination, means a phenyl or a naphthyl group. Preferred is a phenyl group. An “optionally substituted aryl” group means an aryl group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl and (C₁-C₄)fluoro-alkoxy. Preferred are phenyl groups which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy.

Examples of such optionally substituted aryl groups are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2-chloro-phenyl, 4-chloro-phenyl, 2-fluoro-5-chloro-phenyl, 2-methyl-phenyl and 2-methoxy-phenyl. In a preferred embodiment, in case Z represents —NH—, the term “optionally substituted aryl” preferably means a phenyl group which is unsubstituted or mono-substituted, wherein the substituent is selected from halogen or (C₁-C₄)alkoxy. In another preferred embodiment, in case Z represents —O—, the term “optionally substituted aryl” preferably means a phenyl group which is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl (and preferably a phenyl group which is unsubstituted or mono- or di-substituted with halogen). In still another preferred embodiment, in case Z represents a bond, the term “optionally substituted aryl” means a phenyl group, which group is independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl (and preferably a phenyl group, which group is unsubstituted or mono-substituted with halogen, (C₁-C₄)alkyl or (C₁-C₄)alkoxy).

In case “R⁸” represents “(C₂-C₃)alkenyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. An example of such an optionally substituted aryl group is phenyl.

In case “R⁸” represents “(C₃-C₆)cycloalkyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferred is a phenyl group which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Examples of such optionally substituted aryl groups are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,4-dichloro-phenyl, 2-methyl-phenyl, 4-methoxy-phenyl and 2-trifluoromethyl-phenyl.

The term “optionally substituted diphenylmethyl” refers to a methyl group which is substituted with two phenyl groups, which phenyl groups are independently unsubstituted or mono-substituted with halogen. An example is 1-(4-chloro-phenyl)-1-phenyl-methyl.

The term “aryloxy”, used alone or in combination, refers to an aryl-O— group wherein the aryl group is as defined before. An “optionally substituted aryloxy” group means an aryloxy group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with optionally substituted aryloxy” the term “optionally substituted aryloxy” means a phenyloxy or naphthyloxy group, which groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferred is a phenyloxy group which is unsubstituted or mono-substituted with halogen. Examples of such optionally substituted aryloxy groups are phenoxy and 4-fluoro-phenoxy.

The term “optionally substituted aryl-(C₁-C₂)alkoxy”, used alone or in combination, refers to an aryl-(C₁-C₂)alkoxy group as defined above wherein the aryl group is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with optionally substituted aryl-(C₁-C₂)alkoxy” the term “optionally substituted aryl-(C₁-C₂)alkoxy” means the above-mentioned groups, wherein the term “aryl” means a phenyl or a naphthyl group. The aryl groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. A preferred aryl group is a phenyl group which is unsubstituted or mono-substituted with halogen. An example of such an aryl group is 2-chloro-phenyl.

The term “heteroaryl”, used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. Preferred is a 5- to 10-membered monocyclic or bicyclic aromatic ring containing a nitrogen atom and optionally one additional heteroatom selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl. An “optionally substituted heteroaryl” group means an heteroaryl group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred examples of such heteroaryl groups are thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, indolyl, indazolyl and benzisoxazolyl. A preferred example, in case Z represents —N—, is pyridyl (notably pyridin-2-yl). Preferred examples, in case Z represents —O—, are thiazolyl (notably thiazol-4-yl and thiazol-5-yl), pyrazolyl (notably pyrazol-5-yl), pyridyl (notably pyridin-2-yl), pyrimidyl (notably pyrimidin-5-yl) and pyrazinyl (notably pyrazin-2-yl). Preferred examples, in case Z represents a bond, are thiazolyl (notably thiazol-2-yl), pyridyl (notably pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidyl (notably pyrimidin-2-yl), pyrazinyl (notably pyrazin-2-yl), indolyl (notably indol-1-yl and indol-3-yl), indazolyl (notably indazol-1-yl and indazol-3-yl) and benzisoxazolyl (notably benzisoxazol-3-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the heteroaryl groups are independently unsubstituted, mono- or di-substituted wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Examples of such optionally substituted heteroaryl groups are thiazol-2-yl, 2-methyl-thiazol-4-yl, 2-methyl-thiazol-5-yl, 4-methyl-thiazol-5-yl, 1-methyl-pyrazol-5-yl, 1,3-dimethyl-pyrazol-5-yl, pyridin-2-yl, 6-methyl-pyridin-2-yl, 3-methoxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl, 3-fluoro-5-methyl-pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methyl-indol-1-yl, 1-methyl-indol-3-yl, 2-methyl-indol-3-yl, 5-methoxy-indol-3-yl, indazol-1-yl, 3-methyl-indazol-1-yl, 5-fluoro-indazol-1-yl, indazol-3-yl, benzisoxazol-3-yl and 5-methoxy-benzisoxazol-3-yl. In case “R⁸” represents “(C₂-C₃)alkenyl which is mono-substituted with optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred examples of such heteroaryl groups are thiazolyl (notably thiazol-5-yl), pyrazolyl (notably pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl) and benzothiazolyl (notably benzothiazol-2-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferred heteroaryl groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Examples of such optionally substituted heteroaryl groups are 2,4-dimethyl-thiazol-5-yl, 1-methyl-pyrazol-3-yl, 1-methyl-pyrazol-4-yl, 1,3-dimethyl-pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, 6-methoxy-pyridin-3-yl and benzothiazol-2-yl.

In case “R⁸” represents “(C₃-C₆)cycloalkyl which is mono-substituted with optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. A preferred example of such a heteroaryl group is pyridyl (notably pyridin-2-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. A preferred heteroaryl group is unsubstituted. An example of such a optionally substituted heteroaryl group is pyridin-2-yl.

The term “heteroaryloxy”, used alone or in combination, refers to an heteroaryl-O— group wherein the heteroaryl group is as defined before. An “optionally substituted heteroaryloxy” group means a heteroaryloxy group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with optionally substituted heteroaryloxy” the term “optionally substituted heteroaryloxy” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroaryloxy groups containing in the heteroaryl moiety 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryloxy groups are furanyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thienyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy and pyrazinyloxy. A preferred example of such a heteroaryloxy group is pyridyloxy (notably pyridin-3-yloxy). The heteroaryloxy groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. A preferred heteroaryl group is unsubstituted. An example of such an optionally substituted heteroaryloxy group is pyridin-3-yloxy.

The term “heterocyclyl”, used alone or in combination, refers to a saturated monocyclic moiety of 5 to 7 ring members containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, it being understood that a heterocyclyl group does not contain 2 sulfur atoms. The sulfur atom of a heterocyclyl group may be in an oxidised form, i.e. as a sulfoxide or sulfonyl. A heterocyclyl group may optionally be annelated to a benzene ring or a pyridine ring, wherein the benzene ring is optionally mono-substituted with fluoro. An “optionally substituted heterocyclyl” group means a heterocyclyl group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “heterocyclyl” the term means the above-mentioned groups. Preferred are heterocyclyl groups with 5 or 6 ring members containing 1 heteroatom selected from nitrogen and oxygen (preferred) which are annelated to a benzene ring.

Examples of such heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl, isochromanyl, dihydrobenzooxazinyl, dihydrobenzothiazinyl, dihydrobenzodioxinyl and 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl. Preferred examples are chromanyl (notably chroman-2-yl, chroman-3-yl and chroman-4-yl) and isochromanyl (notably isochroman-1-yl and isochroman-3-yl). The heterocyclyl groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, oxo and (C₁-C₄)alkyl. Preferred heterocyclyl groups are unsubstituted. Examples of such optionally substituted heterocyclyl groups are chroman-2-yl, chroman-3-yl, chroman-4-yl, isochroman-1-yl and isochroman-3-yl. In case “R⁸” represents “(C₁-C₅)alkyl which is substituted with optionally substituted heterocyclyl” the term “heterocyclyl” means the above-mentioned groups. Preferred are heterocyclyl groups with 5 or 6 ring members containing 1 heteroatom selected from nitrogen and oxygen which are annelated to a benzene ring or a pyridine ring, wherein the benzene ring is optionally mono-substituted with fluoro. Examples of such heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl, isochromanyl, dihydrobenzooxazinyl, dihydrobenzothiazinyl, dihydrobenzodioxinyl and 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl. Preferred examples are tetrahydrofuranyl (tetrahydrofuran-2-yl), indolinyl (notably indolin-1-yl), dihydrobenzofuranyl (notably dihydrobenzofuran-3-yl), dihydroisobenzofuranyl (notably dihydroisobenzofuran-1-yl), chromanyl (notably chroman-3-yl and chroman-4-yl), isochromanyl (notably isochroman-1-yl and isochroman-4-yl), tetrahydroquinolinyl (notably 1,2,3,4-tetrahydroquinolin-1-yl), tetrahydroisoquinolinyl (notably 1,2,3,4-tetrahydroisoquinolin-1-yl) and 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl (notably 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl). The heterocyclyl groups are independently unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, oxo and (C₁-C₄)alkyl. Examples of such optionally substituted heterocyclyl groups are tetrahydrofuran-2-yl, indolin-1-yl, dihydrobenzofuran-3-yl, dihydroisobenzofuran-1-yl, chroman-3-yl, chroman-4-yl, 6-fluoro-chroman-4-yl, 7-fluoro-chroman-4-yl, 8-fluoro-chroman-4-yl, 2,2-dimethyl-chroman-4-yl, isochroman-1-yl, isochroman-4-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl and 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl.

The following paragraphs provide definitions of the various chemical moieties for the compounds of formula I_(P) and are intended to apply to those compounds unless an otherwise expressly set out definition provides a broader or narrower definition.

The term “alkyl”, used alone or in combination, refers to a straight or branched chain alkyl group containing one to five carbon atoms. The term “(C_(x)-C_(y))alkyl” (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkyl group contains from one to four carbon atoms. Representative examples of (C₁-C₄)alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Representative examples of (C₂-C₅)alkyl groups include ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl and 2,2-dimethyl-prop-1-yl. The alkyl group may be unsubstituted or substituted as explicitly defined.

In case “R¹” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl and ethyl and most preferred is methyl.

In case “R⁷” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl and ethyl and most preferred is methyl.

In case “R⁸” represents “(C₂-C₅)alkyl” the term means (C₂-C₅)alkyl groups as defined above. Examples of said groups are ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl and 2,2-dimethyl-prop-1-yl. Preferred are ethyl, n-propyl, iso-propyl, iso-butyl, tert-butyl and 2,2-dimethyl-prop-1-yl.

In case “R⁸” represents mono- or di-substituted (C₁-C₄)alkyl the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl, ethyl, n-propyl, iso-propyl and sec-butyl; most preferred are methyl and ethyl. The (C₁-C₄)alkyl group is substituted as explicitly defined.

In case “(C₁-C₄)alkyl” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl and ethyl; most preferred is methyl.

The term “carboxy-(C_(x)-C_(y))alkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one hydrogen atom has been replaced with —COOH. For example a carboxy-(C₁-C₃)alkyl group contains from one to three carbon atoms in which one hydrogen atom has been replaced with —COOH. Representative examples of carboxy-(C₁-C₃)alkyl groups include carboxy-methyl, 1-carboxy-ethyl, 2-carboxy-ethyl, 1-carboxy-propyl, 2-carboxy-propyl and 3-carboxy-propyl. Preferred are carboxy-methyl and 1-carboxy-ethyl and most preferred is carboxy-methyl.

The term “(C_(x)-C_(y))fluoroalkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro. For example a (C₁-C₄)fluoroalkyl group contains from one to four carbon atoms in which one to nine hydrogen atoms have been replaced with fluoro.

In case “R¹” represents “(C₁-C₄)fluoroalkyl” the term means a (C₁-C₄)fluoroalkyl group as defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

In case “R⁷” represents “(C₁-C₄)fluoroalkyl” the term means a (C₁-C₄)fluoroalkyl group as defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

In case “(C₁-C₄)fluoroalkyl” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)fluoroalkyl” means (C₁-C₄)fluoroalkyl groups as defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

The term “alkenyl”, used alone or in combination, refers to a straight or branched chain alkenyl group containing two to three carbon atoms. The term “(C_(x)-C_(y))alkenyl” (x and y each being an integer), refers to an alkenyl group as defined before containing x to y carbon atoms. For example a (C₂-C₃)alkenyl group contains from two to three carbon atoms. Representative examples of (C₂-C₃)alkenyl groups include ethenyl and propenyl. Preferred is ethenyl. The (C₂-C₃)alkenyl group is substituted as explicitly defined.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O— group wherein the alkyl group is as defined before. The term “(C_(x)-C_(y))alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkoxy group contains from one to four carbon atoms. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy.

In case “R¹” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R³” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁴” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁵” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁶” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁷” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred are methoxy, ethoxy, n-propoxy, iso-propoxy and iso-butoxy. More preferred are methoxy, ethoxy and n-propoxy and most preferred is methoxy.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with (C₁-C₄)alkoxy” the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred are methoxy and ethoxy. Most preferred is ethoxy.

In case “(C₁-C₄)alkoxy” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

The term “aryl-(C₁-C₂)alkoxy” refers to an (C₁-C₂)alkoxy group as defined above in which one hydrogen atom has been replaced with an aryl group as defined below. Examples of aryl-(C₁-C₂)alkoxy groups are aryl-methoxy, 1-aryl-ethoxy and 2-aryl-ethoxy. Preferred is aryl-methoxy.

The term “carboxy-(C_(x)-C_(y))alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms in which one hydrogen atom has been replaced with —COOH. For example a carboxy-(C₁-C₃)alkoxy group contains from one to three carbon atoms in which one hydrogen atom has been replaced with —COOH. Representative examples of carboxy-(C₁-C₃)alkoxy groups include carboxy-methoxy, 1-carboxy-ethoxy, 2-carboxy-ethoxy, 1-carboxy-propoxy, 2-carboxy-propoxy and 3-carboxy-propoxy. Preferred are carboxy-methoxy and 3-carboxy-propoxy and most preferred is carboxy-methoxy.

The term “(C_(x)-C_(y))fluoroalkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro. For example a (C₁-C₄)fluoroalkoxy group contains from one to four carbon atoms in which one to nine hydrogen atoms have been replaced with fluoro.

In case “R⁷” represents “(C₁-C₄)fluoroalkoxy” the term means a (C₁-C₄)fluoroalkoxy group as defined above. Examples of said groups are difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred is trifluoromethoxy.

In case “(C₁-C₄)fluoroalkoxy” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term “(C₁-C₄)fluoroalkoxy” means (C₁-C₄)fluoroalkoxy groups as defined above. Examples of said groups are difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred is trifluoromethoxy.

The term “(C₁-C₄)alkylsulfonyl”, used alone or in combination, refers to an alkyl-S(O)₂— group wherein the alkyl group is as defined before, which is attached to the rest of the molecule via the sulfur-atom. The term “(C_(x)-C_(y))alkylsulfonyl” (x and y each being an integer) refers to an alkylsulfonyl group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkylsulfonyl group contains from one to four carbon atoms. Representative examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

In case “R¹” represents “(C₁-C₄)alkylsulfonyl” the term means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred is methylsulfonyl.

In case “R⁷” represents “(C₁-C₄)alkylsulfonyl” the term means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred are methylsulfonyl and ethylsulfonyl; most preferred is methylsulfonyl.

The term “halogen” means fluoro, chloro, bromo or iodo.

In case “R¹” represents “halogen” the term means preferably fluoro, chloro or bromo; more preferably fluoro or chloro; and most preferably fluoro.

In case “R²” represents “halogen” the term means preferably fluoro or chloro and most preferably fluoro.

In case “R³” represents “halogen” the term means preferably fluoro or chloro and most preferably fluoro.

In case “R⁴” represents “halogen” the term means preferably fluoro or chloro and most preferably chloro.

In case “R⁵” represents “halogen” the term means preferably fluoro or chloro and most preferably fluoro.

In case “R⁶” represents “halogen” the term means preferably fluoro, chloro or bromo; more preferably fluoro or chloro; and most preferably fluoro.

In case “R⁷” represents “halogen” the term means preferably fluoro, chloro or bromo; more preferably fluoro or chloro; and most preferably chloro.

In case “halogen” is a substituent to a (C₃-C₆)cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy or an aryl-(C₁-C₂)alkoxy group, the term means fluoro, chloro, bromo or iodo; preferably fluoro or chloro; and most preferably fluoro.

The term “oxo” means an oxygen atom which is attached to a carbon atom via a double bond.

The term “cycloalkyl”, used alone or in combination, refers to a cycloalkyl group containing three to six carbon atoms. The term “(C_(x)-C_(y))cycloalkyl” (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C₃-C₆)cycloalkyl group contains from three to six carbon atoms. A cycloalkyl group containing four, five or six carbon atoms may optionally be annelated to a benzene ring. Examples of (C₃-C₆)cycloalkyl groups are cyclopropyl, cyclobutyl, bicyclo[4.2.0]octa-1,3,5-trienyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. Preferred are cyclopropyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. The cycloalkyl group may be unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with optionally substituted (C₃-C₆)cycloalkyl” the term “(C₃-C₆)cycloalkyl” means (C₃-C₆)cycloalkyl groups as defined above. Examples of said groups are cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. Preferred are indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl; more preferred are indanyl and cyclohexyl; and most preferred is indanyl (especially indan-2-yl). The (C₃-C₆)cycloalkyl groups are unsubstituted or mono-substituted with (C₁-C₄)alkyl, (C₁-C₄)alkoxy or hydroxy (preferably hydroxy).

In case “R⁸” represents “(C₃-C₆)cycloalkyl” the term means (C₃-C₆)cycloalkyl groups as defined above. Examples of said groups are cyclopropyl, cyclobutyl, bicyclo[4.2.0]octa-1,3,5-trienyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. Preferred are cyclopropyl, bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl and 1,2,3,4-tetrahydronaphthyl; more preferred are cyclopropyl, indanyl and 1,2,3,4-tetrahydronaphthyl; and most preferred is cyclopropyl. The (C₃-C₆)cycloalkyl groups may be unsubstituted or substituted as explicitly defined.

The term “aryl”, used alone or in any combination, means a phenyl or a naphthyl group. Preferred is a phenyl group. An “optionally substituted aryl” group means an aryl group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl and (C₁-C₄)fluoro-alkoxy. Preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. More preferably the substituents are independently selected from the group consisting of halogen and (C₁-C₄)alkoxy and most preferably from halogen. Examples of such optionally substituted aryl groups are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-difluoro-phenyl, 2-chloro-phenyl, 4-chloro-phenyl, 2-methyl-phenyl and 2-methoxy-phenyl. In a preferred embodiment, in case Z represents —NH—, the term “optionally substituted aryl” preferably means a phenyl group which is unsubstituted or mono-substituted, wherein the substituent is selected from halogen or (C₁-C₄)alkoxy (especially from fluoro, chloro or methoxy). In another preferred embodiment, in case Z represents —O—, the term “optionally substituted aryl” preferably means a phenyl group which is unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl and preferably from halogen (especially fluoro). In still another preferred embodiment, in case Z represents a bond, the term “optionally substituted aryl” means a phenyl group, which group is independently unsubstituted, mono- or di-substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl and preferably from halogen and (C₁-C₄)alkyl (especially from fluoro, chloro and methyl).

In case “R⁸” represents “(C₂-C₃)alkenyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen and (C₁-C₄)alkyl. An examples of such an optionally substituted aryl group is phenyl.

In case “R⁸” represents “(C₃-C₆)cycloalkyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)fluoroalkyl. Examples of such optionally substituted aryl groups are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,4-dichloro-phenyl, 2-methyl-phenyl, 4-methoxy-phenyl and 2-trifluoromethyl-phenyl, (and especially phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-methyl-phenyl and 2-trifluoromethyl-phenyl).

The term “aryloxy”, used alone or in combination, refers to an aryl-O— group wherein the aryl group is as defined before. An “optionally substituted aryloxy” group means an aryloxy group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with optionally substituted aryloxy” the term “optionally substituted aryloxy” means the above-mentioned groups (preferably phenoxy), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from halogen (especially fluoro). Examples of such optionally substituted aryloxy groups are phenoxy and 4-fluoro-phenoxy.

The term “optionally substituted aryl-(C₁-C₂)alkoxy”, used alone or in combination, refers to an aryl-(C₁-C₂)alkoxy group as defined above wherein the aryl group is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with optionally substituted aryl-(C₁-C₂)alkoxy” the term “optionally substituted aryl-(C₁-C₂)alkoxy” means the above-mentioned groups, wherein the term “aryl” means a phenyl or a naphthyl group (preferably a phenyl group). The aryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from halogen (especially chloro). An example of such an aryl group is 2-chloro-phenyl.

The term “heteroaryl”, used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms (preferably 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl. Preferred examples of such heteroaryl groups are thiazolyl (notably thiazol-4-yl and thiazol-5-yl), pyrazolyl (notably pyrazol-5-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl), pyrimidyl (notably pyrimidin-2-yl and pyrimidin-5-yl), indolyl (notably indol-1-yl and indol-3-yl), indazolyl (notably indazol-1-yl and indazol-3-yl), benzisoxazolyl (notably benzisoxazol-3-yl) and benzothiazolyl (notably benzothiazol-2-yl). An “optionally substituted heteroaryl” group means an heteroaryl group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred examples of such heteroaryl groups are thiazolyl (notably thiazol-4-yl and thiazol-5-yl), pyrazolyl (notably pyrazol-5-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl), pyrimidyl (notably pyrimidin-2-yl and pyrimidin-5-yl), indolyl (notably indol-1-yl and indol-3-yl), indazolyl (notably indazol-1-yl and indazol-3-yl) and benzisoxazolyl (notably benzisoxazol-3-yl). Most preferred examples are thiazolyl (notably thiazol-4-yl and thiazol-5-yl), pyrazolyl (notably pyrazol-5-yl), indolyl (notably indol-1-yl and indol-3-yl) and indazolyl (notably indazol-1-yl and indazol-3-yl). Preferred examples, in case X represents —O—, are thiazolyl (notably thiazol-4-yl and thiazol-5-yl), pyrazolyl (notably pyrazol-5-yl) and pyrimidyl (notably pyrimidin-5-yl). Preferred examples, in case X represents a bond, are pyridyl (notably pyridin-2-yl and pyridin-3-yl), pyrimidyl (notably pyrimidin-2-yl), indolyl (notably indol-1-yl and indol-3-yl), indazolyl (notably indazol-1-yl and indazol-3-yl) and benzisoxazolyl (notably benzisoxazol-3-yl); most preferred, in case X represents a bond, are indolyl (notably indol-1-yl and indol-3-yl) and indazolyl (notably indazol-1-yl and indazol-3-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Most preferably the substituents are independently selected from the group consisting of halogen and (C₁-C₄)alkyl. Examples of such optionally substituted heteroaryl groups are 2-methyl-thiazol-4-yl (preferred), 2-methyl-thiazol-5-yl (preferred), 4-methyl-thiazol-5-yl, 1-methyl-pyrazol-5-yl, 1,3-dimethyl-pyrazol-5-yl (preferred), pyridin-2-yl, 6-methyl-pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, 3-methyl-indol-1-yl, 1-methyl-indol-3-yl (preferred), 2-methyl-indol-3-yl (preferred), 5-methoxy-indol-3-yl, indazol-1-yl, 3-methyl-indazol-1-yl, 5-fluoro-indazol-1-yl (preferred), indazol-3-yl, benzisoxazol-3-yl and 5-methoxy-benzisoxazol-3-yl.

In case “R⁸” represents “(C₂-C₃)alkenyl which is mono-substituted with optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred examples of such heteroaryl groups are thiazolyl (notably thiazol-5-yl), pyrazolyl (notably pyrazol-5-yl), pyridyl (notably pyridin-3-yl) and benzothiazolyl (notably benzothiazol-2-yl). A most preferred example is benzothiazolyl (notably benzothiazol-2-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Examples of such optionally substituted heteroaryl groups are 2,4-dimethyl-thiazol-5-yl, 1,3-dimethyl-pyrazol-5-yl, pyridin-3-yl, 6-methoxy-pyridin-3-yl and benzothiazol-2-yl (preferred).

The term “heteroaryloxy”, used alone or in combination, refers to an heteroaryl-O— group wherein the heteroaryl group is as defined before. An “optionally substituted heteroaryloxy” group means a heteroaryloxy group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with optionally substituted heteroaryloxy” the term “optionally substituted heteroaryloxy” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroaryloxy groups containing in the heteroaryl moiety 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroaryloxy groups are furanyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thienyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy and pyrazinyloxy. A preferred example of such heteroaryloxy group is pyridyloxy (notably pyridin-3-yloxy). The heteroaryloxy groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of (C₁-C₄)alkyl and (C₁-C₄)alkoxy. An example of such an optionally substituted heteroaryloxy group is pyridin-3-yloxy.

The term “heterocyclyl”, used alone or in combination, refers to a saturated monocyclic moiety of 5 to 7 ring members containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, it being understood that a heterocyclyl group does not contain 2 sulfur atoms. The sulfur atom of a heterocyclyl group may be in an oxidised form, i.e. as a sulfoxide or sulfonyl. A heterocyclyl group may optionally be annelated to a benzene ring. An “optionally substituted heterocyclyl” group means a heterocyclyl group as defined before which is unsubstituted or substituted as explicitly defined.

In case “R⁸” represents “heterocyclyl” the term means the above-mentioned groups. Preferred are heterocyclyl groups with 5 or 6 ring members containing 1 heteroatom selected from nitrogen and oxygen (preferred) which are annelated to a benzene ring. Examples of such heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl, dihydrobenzooxazinyl, dihydrobenzothiazinyl and dihydrobenzodioxinyl. A preferred example is chromanyl (notably chroman-2-yl and chroman-3-yl). The heterocyclyl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, oxo and (C₁-C₄)alkyl. Examples of such optionally substituted heterocyclyl groups are chroman-2-yl and chroman-3-yl.

In case “R⁸” represents “(C₁-C₄)alkyl which is substituted with optionally substituted heterocyclyl” the term “heterocyclyl” means the above-mentioned groups. Preferred are heterocyclyl groups with 5 or 6 ring members containing 1 heteroatom selected from nitrogen (preferred) and oxygen which are annelated to a benzene ring. Examples of such heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl, dihydrobenzooxazinyl, dihydrobenzothiazinyl and dihydrobenzodioxinyl. Preferred examples are indolinyl (notably indolin-1-yl) and tetrahydroquinolinyl (notably 1,2,3,4-tetrahydroquinolin-1-yl). The heterocyclyl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, oxo and (C₁-C₄)alkyl. Examples of such optionally substituted heterocyclyl groups are indolin-1-yl and 1,2,3,4-tetrahydroquinolin-1-yl.

2) A further embodiment of the invention relates to compounds of formula (I) according to embodiment 1), which are also compounds of formula (I_(P))

wherein

R¹ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)alkylsulfonyl, halogen or cyano;

R² represents hydrogen or halogen;

one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy and the other two represent independently of each other hydrogen, (C₁-C₄)alkoxy or halogen;

R⁶ represents hydrogen, (C₁-C₄)alkoxy or halogen;

R⁷ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, cyclopropylmethoxy, methoxy-ethoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)fluoroalkoxy, halogen or (C₁-C₄)alkylsulfonyl;

or R⁶ and R⁷ together represent methylendioxy or ethylendioxy;

R⁸ represents

-   -   (C₂-C₅)alkyl;     -   (C₁-C₄)alkyl which is mono- or di-substituted wherein the         substituents are independently selected from the group         consisting of (C₁-C₄)alkoxy, oxo, optionally substituted         (C₃-C₆)cycloalkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy or optionally substituted aryl-(C₁-C₂)alkoxy;     -   (C₂-C₃)alkenyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl;     -   (C₃-C₆)cycloalkyl which is unsubstituted, mono-, di-, tri- or         tetra-substituted with methyl; mono-substituted with oxo; or         mono-substituted with optionally substituted aryl; or     -   heterocyclyl which is optionally mono-substituted with oxo;

n represents 1 or 2;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

3) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents hydrogen, methyl, trifluoromethyl, halogen or cyano;

R² represents hydrogen or halogen;

one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy, another one of R³, R⁴ and R⁵ represents hydrogen, (C₁-C₄)alkoxy or halogen and the third one of R³, R⁴ and R⁵ represents hydrogen;

R⁶ represents hydrogen, methoxy or halogen;

R⁷ represents hydrogen, (C₁-C₄)alkoxy, trifluoromethyl, trifluoromethoxy, halogen or methylsulfonyl;

or R⁶ and R⁷ together represent methylendioxy or ethylendioxy;

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted (C₅-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy or optionally         substituted aryl-(C₁-C₂)alkoxy;     -   (C₂-C₃)alkenyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

n represents 1 or 2;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

4) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents hydrogen or halogen;

R² represents hydrogen or halogen (preferably hydrogen or fluoro);

one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy (preferably carboxy-methyl, 1-carboxy-ethyl or carboxy-methoxy) and the other two represent hydrogen;

R⁶ represents hydrogen, methoxy or halogen (preferably hydrogen, fluoro or chloro);

R⁷ represents hydrogen, (C₁-C₄)alkoxy, trifluoromethyl, trifluoromethoxy, halogen or methylsulfonyl (preferably hydrogen, (C₁-C₄)alkoxy or halogen);

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl or         optionally substituted aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

n represents 1 or 2;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

5) A further embodiment of the invention relates to compounds according to embodiment 1), wherein

R¹ represents hydrogen, fluoro, chloro or cyano;

R² represents hydrogen or fluoro;

one of R³, R⁴ and R⁵ represents carboxy-methyl, 1-carboxy-ethyl or carboxy-methoxy and the other two represent hydrogen;

R⁶ represents hydrogen;

R⁷ represents (C₁-C₄)alkoxy, cyclopropyl-methoxy, cyclopropyloxy, methoxy-ethoxy or (C₁-C₄)fluoroalkoxy;

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted (C₃-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy or optionally         substituted aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl; or mono-substituted with optionally         substituted heteroaryl;

n represents 1;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

6) A further embodiment of the invention relates to compounds according to embodiment 1), wherein

R¹ represents fluoro;

R², R³ and R⁶ represent hydrogen;

one of R⁴ and R⁵ represents carboxy-methyl and the other represents hydrogen;

R⁷ represents methoxy, ethoxy, n-propoxy, iso-propoxy, iso-butoxy, tert-butoxy, cyclopropyl-methoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy;

R⁸ represents a methyl, ethyl or n-propyl group, which groups are independently mono-substituted with

-   -   phenyl, wherein the phenyl is unsubstituted or mono-substituted         with fluoro, chloro or methoxy; or     -   pyridin-2-yl, wherein the pyridin-2-yl is unsubstituted,         mono-substituted with methyl, or di-substituted with methyl and         fluoro;

n represents 1;

m represents 2; and

Z represents —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

7) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents hydrogen or halogen (preferably hydrogen or fluoro);

R² represents hydrogen;

R³ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy (preferably carboxy-methyl, carboxy-methoxy or carboxy-propoxy);

R⁴ represents hydrogen;

R⁵ represents hydrogen;

R⁶ represents hydrogen or halogen (preferably fluoro or chloro);

R⁷ represents hydrogen or methoxy (notably hydrogen);

R⁸ represents (C₁-C₄)alkyl (preferably methyl) which is mono-substituted with optionally substituted aryl;

n represents 1;

m represents 2; and

Z represents —NH—, —O— or a bond (preferably —O—);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

8) A further embodiment of the invention relates to compounds according to embodiment 1), wherein

R¹ represents fluoro;

R², R⁴ and R⁶ represent hydrogen;

R³ represents hydrogen or (C₁-C₄)alkoxy;

R⁵ represents carboxy-methyl or 1-carboxy-ethyl;

R⁷ represents (C₁-C₄)alkoxy or (C₁-C₄)fluoroalkoxy;

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted (C₃-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy or optionally         substituted aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with phenyl or pyridyl;

n represents 1;

m represents 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

9) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents hydrogen or halogen;

R² represents hydrogen or fluoro (preferably hydrogen);

R³ represents hydrogen;

R⁴ represents hydrogen;

R⁵ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy (preferably carboxy-methyl or carboxy-methoxy);

R⁶ represents hydrogen or halogen;

R⁷ represents hydrogen, (C₁-C₄)alkoxy or halogen (preferably hydrogen, methoxy or halogen);

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted aryloxy or optionally substituted         aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

n represents 1 or 2 (preferably 1);

m represents 1 or 2 (preferably 2); and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

10) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents hydrogen or halogen (preferably fluoro);

R² represents hydrogen;

R³ represents hydrogen;

R⁴ represents hydrogen;

R⁵ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy (preferably carboxy-methyl or carboxy-methoxy);

R⁶ represents hydrogen, fluoro or chloro (preferably hydrogen or chloro);

R⁷ represents hydrogen, methoxy or halogen (preferably hydrogen, methoxy, fluoro or chloro);

R⁸ represents (C₁-C₄)alkyl (preferably methyl) which is mono-substituted with optionally substituted aryl;

n represents 1;

m represents 2; and

Z represents —O— or a bond (preferably —O—);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

11) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents fluoro;

R², R³, R⁴ and R⁶ represent hydrogen;

R⁵ represents carboxy-methyl or 1-carboxy-ethyl;

R⁷ represents methoxy, ethoxy, isopropoxy or 2,2,2-trifluoroethoxy;

R⁸ represents a methyl, ethyl or n-propyl group, which groups are independently mono-substituted with

-   -   phenyl, wherein the phenyl is unsubstituted, mono-substituted         with fluoro, chloro, methyl or methoxy, di-substituted with         fluoro, or di-substituted with fluoro and chloro; or     -   pyridin-2-yl, wherein the pyridin-2-yl is unsubstituted,         mono-substituted with methyl, or di-substituted with methyl and         fluoro;

n represents 1;

m represents 2; and

Z represents —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

12) A further embodiment of the invention relates to compounds according to embodiment 1), wherein

R¹ represents hydrogen, fluoro, chloro or cyano;

R² represents hydrogen or fluoro;

R³ represents hydrogen or fluoro;

R⁴ represents carboxy-methyl, 1-carboxy-ethyl, carboxy-cyclopropyl or carboxy-methoxy;

R⁵ represents hydrogen, methoxy, fluoro or chloro;

R⁶ represents hydrogen, methoxy, fluoro or chloro;

R⁷ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, cyclopropyl-methoxy, cyclopropyloxy, methoxy-ethoxy, dimethylamino, trifluoromethyl, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, fluoro, chloro or methyl-sulfonyl; or R⁶ and R⁷ together represent methylendioxy or ethylendioxy;

R⁸ represents

-   -   n-butyl, iso-butyl, 2-methyl-but-1-yl and 3-methyl-but-1-yl;     -   (C₁-C₅)alkyl which is mono-substituted with hydroxy, methoxy,         ethoxy, optionally substituted (C₃-C₆)cycloalkyl, optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted heterocyclyl, optionally substituted aryloxy,         optionally substituted heteroaryloxy or optionally substituted         aryl-(C₁-C₂)alkoxy;     -   3-methyl-2-butenyl and 3-methyl-3-butenyl;     -   ethenyl which is mono-substituted with optionally substituted         aryl or optionally substituted heteroaryl;     -   3-butynyl; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl;

n represents 1 or 2;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

13) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)alkylsulfonyl, halogen or cyano;

R² represents hydrogen or halogen;

R³ represents hydrogen or halogen;

R⁴ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy;

R⁵ represents hydrogen, (C₁-C₄)alkoxy or halogen;

R⁶ represents hydrogen, (C₁-C₄)alkoxy or halogen;

R⁷ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, cyclopropylmethoxy, methoxy-ethoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)fluoroalkoxy, halogen or (C₁-C₄)alkylsulfonyl;

or R⁶ and R⁷ together represent methylendioxy or ethylendioxy;

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted (C₃-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy, optionally         substituted heteroaryloxy or optionally substituted         aryl-(C₁-C₂)alkoxy;     -   (C₂-C₃)alkenyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl;     -   (C₃-C₆)cycloalkyl which is unsubstituted, mono-, di-, tri- or         tetra-substituted with methyl; mono-substituted with oxo; or         mono-substituted with optionally substituted aryl; or     -   heterocyclyl;

n represents 1 or 2;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

14) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents hydrogen, methyl, methoxy, trifluoromethyl, halogen or cyano (preferably hydrogen, fluoro or chloro);

R² represents hydrogen or fluoro;

R³ represents hydrogen or fluoro;

R⁴ represents carboxy-methyl, 1-carboxy-ethyl or carboxy-methoxy;

R⁵ represents hydrogen, methoxy, fluoro or chloro;

R⁶ represents hydrogen, methoxy, fluoro or chloro;

R⁷ represents hydrogen, methyl, (C₁-C₄)alkoxy, cyclopropylmethoxy, methoxy-ethoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro or methylsulfonyl;

or R⁶ and R⁷ together represent methylendioxy or ethylendioxy;

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted (C₅-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy or optionally         substituted aryl-(C₁-C₂)alkoxy;     -   (C₂-C₃)alkenyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

n represents 1 or 2;

m represents 1 or 2; and

Z represents —NH—, —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

15) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 2), wherein

R¹ represents fluoro, chloro or cyano;

R², R³, R⁵ and R⁶ represent hydrogen;

R⁴ represents carboxy-methyl or 1-carboxy-ethyl;

R⁷ represents methoxy, ethoxy, n-propoxy, iso-propoxy, iso-butoxy, tert-butoxy, cyclopropyl-methoxy, methoxy-ethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy;

R⁸ represents a methyl, ethyl or n-propyl group, which groups are independently mono-substituted with

-   -   phenyl, wherein the phenyl is unsubstituted, mono-substituted         with fluoro, chloro or methoxy, di-substituted with fluoro, or         di-substituted with fluoro and chloro; or     -   pyridin-2-yl, wherein the pyridin-2-yl is unsubstituted,         mono-substituted with methyl, or di-substituted with methyl and         fluoro;

n represents 1;

m represents 2; and

Z represents —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

16) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 2), 13 or 14), wherein

R¹ represents hydrogen, methyl, trifluoromethyl, halogen or cyano;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

17) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 7), 9), 10) or 12) to 14), wherein R¹ represents hydrogen, fluoro or chloro;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

18) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 15), wherein

R¹ represents fluoro;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

19) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 13) or 16) to 18), wherein

R² represents hydrogen or fluoro;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

20) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 18), wherein

R² represents hydrogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

21) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 20), wherein

one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkyl (preferably carboxy-methyl or 1-carboxy-ethyl and most preferably carboxy-methyl);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

22) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 20), wherein

R⁴ represents carboxy-methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

23) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 20), wherein

R⁵ represents carboxy-methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

24) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 20), wherein

one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkoxy (preferably carboxy-methoxy or 3-carboxy-propoxy and most preferably carboxy-methoxy);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

25) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 20), wherein

R⁴ represents carboxy-methoxy;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

26) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 7), 9), 10), 12) to 14) or 16) to 20), wherein

one of R³, R⁴ and R⁵ represents carboxy-methyl, 1-carboxy-ethyl or carboxy-methoxy; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

27) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5) or 16) to 20), wherein

R³ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy (preferably carboxy-methyl, carboxy-methoxy or 3-carboxy-propoxy);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

28) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5) or 16) to 20), wherein

R⁴ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy (preferably carboxy-methyl, 1-carboxy-ethyl or carboxy-methoxy);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

29) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5) or 16 to 20), wherein

R⁵ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy (preferably carboxy-methyl or carboxy-methoxy and most preferably carboxy-methyl);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

30) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 29), wherein

one or two of R³, R⁴ and R⁵ represent hydrogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

31) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 3), 13) or 16) to 30), wherein

one of R³, R⁴ and R⁵ represents (C₁-C₄)alkoxy or halogen (preferably methoxy, fluoro or chloro);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

32) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4), 13) or 16) to 31), wherein

R⁶ represents hydrogen, methoxy, fluoro or chloro (and preferably methoxy);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

33) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 31), wherein

R⁶ represents hydrogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

34) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4), 13) or 16) to 33), wherein

R⁷ represents hydrogen, (C₁-C₄)alkoxy, trifluoromethyl, trifluoromethoxy, halogen or methylsulfonyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

35) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 8), 12) to 14) or 16) to 33), wherein

R⁷ represents (C₁-C₄)alkoxy or trifluoromethoxy (preferably methoxy, iso-propoxy or trifluoromethoxy);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

36) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4), 9), 12) to 14) or 16) to 33), wherein

R⁷ represents hydrogen, (C₁-C₄)alkoxy or halogen (preferably hydrogen, methoxy, fluoro or chloro);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

37) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4), 7), 9), 10), 12) to 14) or 16) to 22), wherein

R⁷ represents hydrogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

38) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 2), 13) or 16) to 37), wherein

Z represents —NH— and R⁸ represents (C₁-C₄)alkyl (preferably (C₁-C₂)alkyl) which is mono-substituted with optionally substituted aryl; or

Z represents —O— and R⁸ represents (C₁-C₄)alkyl (preferably methyl) which is mono-substituted with optionally substituted aryl or optionally substituted heteroaryl; or

Z represents a bond and R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted (C₃-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy or optionally         substituted aryl-(C₁-C₂)alkoxy;     -   (C₂-C₃)alkenyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl; or     -   (C₃-C₆)cycloalkyl which is unsubstituted or mono-substituted         with optionally substituted aryl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

39) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 3), 5), 9), 12) to 14) or 16) to 37), wherein

Z represents —O— and R⁸ represents (C₁-C₄)alkyl (preferably methyl) which is mono-substituted with optionally substituted aryl or optionally substituted heteroaryl; or

Z represents a bond and R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted aryloxy or optionally substituted aryl-methoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

40) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 3), 13), 14) or 16) to 37), wherein

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted (C₅-C₆)cycloalkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy or optionally         substituted aryl-(C₁-C₂)alkoxy;     -   (C₂-C₃)alkenyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

41) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 9), 12) to 14) or 16) to 37), wherein

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl or         optionally substituted aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

42) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 9), 12) to 14) or 16) to 37), wherein

R⁸ represents

-   -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl or optionally substituted heteroaryl; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

43) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 8), 9), 12) to 14) or 16) to 39), wherein

R⁸ represents (C₁-C₄)alkyl which is mono-substituted with optionally substituted aryl or optionally substituted heteroaryl (preferably mono-substituted with optionally substituted aryl);

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

44) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 9), 12) to 14) or 16) to 37), wherein

R⁸ represents cyclopropyl which is mono-substituted with optionally substituted aryl; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

45) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 3), 5), 8), 12) to 14) or 16) to 37), wherein

R⁸ represents methyl which is mono-substituted with a 2,3-dihydrobenzofuranyl, a chromanyl or an isochromanyl group, which groups are in the aromatic portion optionally mono-substituted with fluorine and in the non-aromatic portion optionally di-substituted with methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

46) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 45), wherein

n represents 1;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

47) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4), 9), 12) to 14) or 16) to 45), wherein

n represents 2;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

48) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 9), 12) to 14) or 16) to 47), wherein

m represents 1;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

49) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 47), wherein

m represents 2;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

50) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 7) to 9), 12) to 14), 16) to 38) or 40) to 49), wherein

Z represents —NH— or —O—;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

51) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 49), wherein

Z represents —O— or a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

52) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), 7) to 9), 12) to 14), 16) to 38) or 40) to 49), wherein

Z represents —NH—;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

53) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 49), wherein

Z represents —O—;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

54) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 49), wherein

Z represents a bond;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

55) Preferred compounds of formula (I) as defined in embodiment 1) are selected from the group consisting of:

-   (3-{5-Fluoro-2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[trans-2-(4-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[trans-2-(2-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[trans-2-(3-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[trans-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   8-(5-Carboxymethyl-2-methyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-trifluoromethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-4-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-4-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-4-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-5-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-5-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   6-(5-Carboxymethyl-2-methoxy-phenyl)-9-fluoro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic     acid benzyl ester; -   4-(5-Carboxymethyl-2-methoxy-phenyl)-7-fluoro-1,3-dihydro-isoindole-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methanesulfonyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-trifluoromethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-trifluoromethoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   {4-Chloro-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methanesulfonyl-phenyl}-acetic     acid; -   8-(2-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-7-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {3-[6-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[7-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[9-Fluoro-3-(trans-2-phenyl-cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[7-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-2,3-dihydro-1H-isoindol-4-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5,7-Difluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-3-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (3-{5-Fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(4-fluoro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-(2-Ethoxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(2-tert-Butoxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[trans-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-pyridin-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   [3-(2-Cyclopropanecarbonyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic     acid; -   {3-[2-(3-3,4-Dihydro-2H-quinolin-1-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(2,2-Dimethyl-cyclopropanecarbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[3-(3-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[(1R,2R)-2-(4-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[(1R,2R)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Chloro-2-[(1R,2R)-2-(4-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Chloro-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Chloro-2-[(1R,2R)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Chloro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Chloro-2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Chloro-2-[2-(2-chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Chloro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Chloro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Chloro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Chloro-2-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Chloro-2-(3-2,3-dihydro-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Chloro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   [3-(2-Cyclopropanecarbonyl-5-trifluoromethyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic     acid; -   {4-Methoxy-3-[2-(trans-2-phenyl-cyclopropanecarbonyl)-5-trifluoromethyl-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-[5,6-Difluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[(E)-(3-phenyl-acryloyl)]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[(E)-3-(6-methoxy-pyridin-3-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[(E)-3-(2,4-Dimethyl-thiazol-5-yl)-acryloyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-((E)-3-Benzothiazol-2-yl-acryloyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((E)-3-pyridin-3-yl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{2-[(E)-3-(2,5-Dimethyl-2H-pyrazol-3-yl)-acryloyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(3-pyrimidin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(pyridin-3-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[trans-2-(4-methoxy-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[3-(4-Chloro-phenyl)-3-phenyl-propionyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[trans-2-(2,4-Dichloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[8-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[8-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[8-Fluoro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[8-Fluoro-2-(3-phenoxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{2-[2-(2-Chloro-benzyloxy)-acetyl]-8-fluoro-1,2,3,4-tetrahydro-isoquinolin-5-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-(3-3,4-Dihydro-2H-quinolin-1-yl-propionyl)-8-fluoro-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{8-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-5-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-methyl-3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(indane-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-indan-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(indane-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(Chroman-3-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(4-oxo-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(Chroman-2-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(Bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(4-oxo-4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(1-methyl-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   2-{3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-propionic     acid; -   {3-[2-(2-Benzo[d]isoxazol-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-oxo-indane-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-1H-indazol-3-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[3-(3-methyl-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-(2-Cyclohexyl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(1-hydroxy-cyclohexyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-(3,3-Dimethyl-butyryl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   [3-(5-Fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic     acid; -   {3-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   [3-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic     acid; -   [3-(5-Fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic     acid; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-fluoro-benzyl ester; -   8-[5-(1-Carboxy-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid ethyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid isobutyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid isopropyl ester; -   8-(3-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,3-difluoro-benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-2H-pyrazol-3-ylmethyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-4-ylmethyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-5-ylmethyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrimidin-5-ylmethyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   5-(5-Carboxymethyl-2-methoxy-phenyl)-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-trifluoromethoxy-phenoxy}-acetic     acid; -   {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenoxy}-acetic     acid; -   8-(5-Carboxymethoxy-2-trifluoromethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethoxy-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(6-Carboxymethyl-benzo[1,3]dioxol-4-yl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(7-Carboxymethyl-2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[5-(1-Carboxy-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[2-(3-Carboxy-propoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethoxy-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethoxy-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethoxy-2-chloro-phenyl)-5-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethoxy-2-chloro-phenyl)-5-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethoxy-2-chloro-phenyl)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethoxy-2-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenoxy}-acetic     acid; -   (4-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic     acid; -   {4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   (4-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic     acid; -   (4-{5-Fluoro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic     acid; -   {4-[5-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   (4-{5-Fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic     acid; -   {4-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   (4-{5-Fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic     acid; -   (4-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic     acid; -   {4-[5-Fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-cyclopropylmethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-propoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-isobutoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; and -   8-[5-Carboxymethyl-2-(2-methoxy-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester;

or salts (in particular pharmaceutically acceptable salts) of such compounds;

it is to be understood for any of the above listed compounds, that a stereogenic center, which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration and that a double bond, which is not specifically assigned, may be in (E)- or (Z)-configuration; notably it is to be understood for any compound listed above which can be separated into atropisomers, that the compound may be a respective atropisomer of formula (I_(St1)), a respective atropisomer of formula (I_(St2)) or any mixture thereof.

56) Further preferred compounds of formula (I) as defined in embodiment 1) are selected from the group consisting of:

-   {4-[2-((S)-2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   {4-[2-((R)-2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   8-[4-(1-Carboxy-ethoxy)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {4-Ethoxy-3-[5-fluoro-2-((S)-3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((R)-3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-((S)-2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-((R)-2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-[2-(2-[(S)-2,3-Dihydro-benzofuran-3-yl]-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic     acid; -   {3-[2-(2-[(R)-2,3-Dihydro-benzofuran-3-yl]-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((S)-2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((R)-2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[(S)-3-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[(R)-3-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((S)-2-methyl-3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((R)-2-methyl-3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   8-(5-Carboxymethyl-2-propyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-2-isopropyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethyl-2,6-dimethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {4-Ethoxy-3-[5-fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic     acid; -   {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic     acid; -   {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[2-(6-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-(3-Cyclopropyl-butyryl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(8-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(2-5,6,7,8-tetrahydro-isoquinolin-8-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[3-(6-methoxy-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[2-(1-phenyl-cyclobutyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   [3-(5-Fluoro-2-{2-[1-(4-fluoro-phenyl)-cyclobutyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic     acid; -   (3-{5-Fluoro-2-[3-(3-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[2-(2-{[(4-Chloro-phenyl)-phenyl-methyl]-methyl-amino}-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(2-Cyclopropyl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((R)-2-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-hydroxy-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[2-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(4-methyl-3-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-pyridin-3-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-pyridin-4-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((R)-1,2,3,4-tetrahydro-naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(Chroman-4-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(isochroman-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(isochroman-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   [4-Ethoxy-3-(5-fluoro-2-{2-[1-(3-fluoro-phenyl)-cyclopropyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic     acid; -   [4-Ethoxy-3-(5-fluoro-2-{2-[1-(2-fluoro-phenyl)-cyclopropyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic     acid; -   [4-Ethoxy-3-(5-fluoro-2-{2-[1-(4-fluoro-phenyl)-cyclopropyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(3-pyrazin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(2-methoxy-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(3-thiazol-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (3-{2-[2-(2,2-Dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-ethoxy-phenyl)-acetic     acid; -   [4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [4-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [4-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   {3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-isopropoxy-phenyl)-acetic     acid; -   (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-isopropoxy-phenyl)-acetic     acid; -   {3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic     acid; -   [3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   [3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(3-methoxy-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[3-(3-methoxy-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[3-(3-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {3-[2-(3-Cyclopropyl-3-pyridin-2-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic     acid; -   {4-[2-(3-Cyclopropyl-3-pyridin-2-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(trans-2-pyridin-2-yl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-ethoxy-phenyl)-acetic     acid; -   {4-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(trans-2-pyridin-2-yl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (3-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-ethoxy-phenyl)-acetic     acid; -   {3-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-((E)-3-pyridin-2-yl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-3-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-((E)-3-pyridin-2-yl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-4-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(2-pyridin-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-4-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(2-pyridin-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(2-methyl-3-pyridin-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic     acid; -   [4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(2-5,6,7,8-tetrahydro-quinolin-8-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic     acid; -   (4-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic     acid; -   {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   {4-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic     acid; -   {3-[5-Fluoro-2-(trans-2-pyridin-2-yl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   {3-[2-(2-1,3-Dihydro-isobenzofuran-1-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic     acid; -   (3-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic     acid; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (R)-1-phenyl-ethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrazin-2-ylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-5-methyl-pyridin-2-ylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-2H-pyrazol-3-ylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (S)-1-phenyl-ethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclopentylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-butyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 6-methyl-pyridin-2-ylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclopropylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid phenethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (R)-2-phenyl-propyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-but-2-enyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid butyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid isobutyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methoxy-ethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-but-3-enyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-butyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid but-3-ynyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-hydroxy-3-methyl-butyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methoxy-3-methyl-butyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid tetrahydro-furan-2-ylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (R)-1-phenyl-ethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrazin-2-ylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-5-methyl-pyridin-2-ylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-2H-pyrazol-3-ylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (S)-1-phenyl-ethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 6-methyl-pyridin-2-ylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclopropylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclopentylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-butyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyridin-2-ylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyridin-2-ylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclohexylmethyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclohexylmethyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-fluoro-benzyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-difluoro-benzyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 5-chloro-2-fluoro-benzyl ester; -   8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,4-difluoro-benzyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-fluoro-benzyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-difluoro-benzyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 5-chloro-2-fluoro-benzyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,4-difluoro-benzyl ester; -   8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[4-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-difluoromethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[5-Carboxymethyl-2-(2,2-difluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[5-(1-Carboxy-ethoxy)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[5-(1-Carboxy-propoxy)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(2-Carboxymethyl-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(2-Carboxymethoxy-6-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(2-Carboxymethyl-6-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(2-tert-Butoxy-5-carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-dimethylamino-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[5-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[5-Carboxymethyl-2-(2-fluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(3-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(4-Carboxymethoxy-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-[4-(1-Carboxy-ethyl)-2-ethoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   [3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic     acid; -   {4-(2-Fluoro-ethoxy)-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-tert-Butoxy-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   1-{3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-cyclopropanecarboxylic     acid; -   8-(5-Carboxymethyl-2-cyclopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {4-Ethoxy-3-[5-fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   [4-Ethoxy-3-(5-fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic     acid; -   {3-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic     acid; -   {4-Ethoxy-3-[5-fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   [3-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-ethoxy-phenyl]-acetic     acid; -   [4-Ethoxy-3-(5-fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   [3-Ethoxy-4-(5-fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic     acid; -   {4-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic     acid; -   {3-Ethoxy-4-[5-fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic     acid; -   [4-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-3-ethoxy-phenyl]-acetic     acid; -   [3-Ethoxy-4-(5-fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic     acid; -   (3-Ethoxy-4-{5-fluoro-2-[(pyridin-2-ylmethyl)-carbamoyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid; and -   (4-Ethoxy-3-{5-fluoro-2-[(pyridin-2-ylmethyl)-carbamoyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic     acid;

or salts (in particular pharmaceutically acceptable salts) of such compounds;

it is to be understood for any of the above listed compounds, that a stereogenic center, which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration and that a double bond, which is not specifically assigned, may be in (E)- or (Z)-configuration; notably it is to be understood for any compound listed above which can be separated into atropisomers, that the compound may be a respective atropisomer of formula (I_(St1)), a respective atropisomer of formula (I_(St2)) or any mixture thereof.

It is well understood that the invention relates to compounds according to embodiment 1); or according to embodiment 1) limited by the features of an embodiment dependent on embodiment 1; or according to embodiment 1) limited by the features of a cascade of dependent embodiments e.g. in the form of “embodiment 9) depending on embodiment 2) depending on embodiment 1)”. In case of an embodiment depending on more than one other embodiment, it is understood that each combination is specifically disclosed. Also, in case an embodiment is dependent on more than one other embodiment and one or more of said other embodiments are themselves dependent on one or more further embodiments, it is understood that each combination is specifically disclosed if obtainable with regard to the given dependencies and multiple dependencies. Notably, embodiments resulting from cascades of more than three embodiments depending on each other may be construed under observance of the given dependencies and multiple dependencies and are thus intended to be specifically disclosed. Representative examples of embodiments which are possible based on the dependencies of the embodiments 1) to 56) as disclosed hereinabove and which are therefore intended and herewith specifically disclosed in individualized form are:

1, 2+1, 3+1, 3+2+1, 4+1, 4+2+1, 5+1, 6+1, 7+1, 7+2+1, 8+1, 9+1, 9+2+1, 10+1, 10+2+1, 11+1, 11+2+1, 12+1, 13+1, 13+2+1, 14+1, 14+2+1, 15+1, 15+2+1, 16+1, 16+2+1, 17+1, 17+2+1, 17+14+1, 17+14+2+1, 18+1, 18+2+1, 18+3+1, 18+3+2+1, 18+4+1, 18+4+2+1, 18+5+1, 18+9+1, 18+9+2+1, 18+10+1, 18+10+2+1, 18+12+1, 18+13+1, 18+13+2+1, 18+14+1, 18+14+2+1, 18+15+1, 18+15+2+1, 19+1, 20+1, 20+2+1, 20+14+1, 20+14+2+1, 20+18+1, 20+18+2+1, 20+18+3+1, 20+18+3+2+1, 20+18+4+1, 20+18+4+2+1, 20+18+5+1, 20+18+9+1, 20+18+9+2+1, 20+18+10+1, 20+18+10+2+1, 20+18+12+1, 20+18+13+1, 20+18+13+2+1, 20+18+14+1, 20+18+14+2+1, 20+18+15+1, 20+18+15+2+1, 21+1, 21+2+1, 21+3+1, 21+3+2+1, 21+4+1, 21+4+2+1, 21+5+1, 22+1, 22+2+1, 22+3+1, 22+3+2+1, 22+4+1, 22+4+2+1, 22+5+1, 22+6+1, 22+12+1, 22+13+1, 22+13+2+1, 22+14+1, 22+14+2+1, 22+15+1, 22+15+2+1, 22+18+1, 22+18+2+1, 22+18+3+1, 22+18+3+2+1, 22+18+4+1, 22+18+4+2+1, 22+18+5+1, 22+18+9+1, 22+18+9+2+1, 22+18+10+1, 22+18+10+2+1, 22+18+12+1, 22+18+13+1, 22+18+13+2+1, 22+18+14+1, 22+18+14+2+1, 22+18+15+1, 22+18+15+2+1, 22+20+1, 22+20+2+1, 22+20+14+1, 22+20+14+2+1, 22+20+18+1, 22+20+18+2+1, 22+20+18+3+1, 22+20+18+3+2+1, 22+20+18+4+1, 22+20+18+4+2+1, 22+20+18+5+1, 22+20+18+9+1, 22+20+18+9+2+1, 22+20+18+10+1, 22+20+18+10+2+1, 22+20+18+12+1, 22+20+18+13+1, 22+20+18+13+2+1, 22+20+18+14+1, 22+20+18+14+2+1, 22+20+18+15+1, 22+20+18+15+2+1, 23+1, 23+2+1, 23+3+1, 23+3+2+1, 23+4+1, 23+4+2+1, 23+5+1, 23+6+1, 23+8+1, 23+9+1, 23+9+2+1, 23+10+1, 23+10+2+1, 23+11+1, 23+11+2+1, 23+18+1, 23+18+2+1, 23+18+3+1, 23+18+3+2+1, 23+18+4+1, 23+18+4+2+1, 23+18+5+1, 23+18+9+1, 23+18+9+2+1, 23+18+10+1, 23+18+10+2+1, 23+18+12+1, 23+18+13+1, 23+18+13+2+1, 23+18+14+1, 23+18+14+2+1, 23+18+15+1, 23+18+15+2+1, 23+20+1, 23+20+2+1, 23+20+14+1, 23+20+14+2+1, 23+20+18+1, 23+20+18+2+1, 23+20+18+3+1, 23+20+18+3+2+1, 23+20+18+4+1, 23+20+18+4+2+1, 23+20+18+5+1, 23+20+18+9+1, 23+20+18+9+2+1, 23+20+18+10+1, 23+20+18+10+2+1, 23+20+18+12+1, 23+20+18+13+1, 23+20+18+13+2+1, 23+20+18+14+1, 23+20+18+14+2+1, 23+20+18+15+1, 23+20+18+15+2+1, 24+1, 24+2+1, 24+3+1, 24+3+2+1, 24+4+1, 24+4+2+1, 24+5+1, 25+1, 25+2+1, 25+3+1, 25+3+2+1, 25+4+1, 25+4+2+1, 25+5+1, 25+12+1, 25+13+1, 25+13+2+1, 25+14+1, 25+14+2+1, 26+1, 27+1, 28+1, 28+2+1, 28+3+1, 28+3+2+1, 28+4+1, 28+4+2+1, 28+5+1, 29+1, 29+2+1, 29+3+1, 29+3+2+1, 29+4+1, 29+4+2+1, 29+5+1, 30+1, 31+1, 32+1, 33+1, 33+2+1, 33+3+1, 33+3+2+1, 33+4+1, 33+4+2+1, 33+9+1, 33+9+2+1, 33+10+1, 33+10+2+1, 33+11+1, 33+11+2+1, 33+12+1, 33+13+1, 33+13+2+1, 33+14+1, 33+14+2+1, 33+20+1, 33+20+2+1, 33+20+14+1, 33+20+14+2+1, 33+20+18+1, 33+20+18+2+1, 33+20+18+3+1, 33+20+18+3+2+1, 33+20+18+4+1, 33+20+18+4+2+1, 33+20+18+5+1, 33+20+18+9+1, 33+20+18+9+2+1, 33+20+18+10+1, 33+20+18+10+2+1, 33+20+18+12+1, 33+20+18+13+1, 33+20+18+13+2+1, 33+20+18+14+1, 33+20+18+14+2+1, 33+20+18+15+1, 33+20+18+15+2+1, 34+1, 35+33+1, 35+33+2+1, 35+33+3+1, 35+33+3+2+1, 35+33+4+1, 35+33+4+2+1, 35+33+9+1, 35+33+9+2+1, 35+33+10+1, 35+33+10+2+1, 35+33+11+1, 35+33+11+2+1, 35+33+12+1, 35+33+13+1, 35+33+13+2+1, 35+33+14+1, 35+33+14+2+1, 35+33+20+1, 35+33+20+2+1, 35+33+20+14+1, 35+33+20+14+2+1, 35+33+20+18+1, 35+33+20+18+2+1, 35+33+20+18+3+1, 35+33+20+18+3+2+1, 35+33+20+18+4+1, 35+33+20+18+4+2+1, 35+33+20+18+5+1, 35+33+20+18+9+1, 35+33+20+18+9+2+1, 35+33+20+18+10+1, 35+33+20+18+10+2+1, 35+33+20+18+12+1, 35+33+20+18+13+1, 35+33+20+18+13+2+1, 35+33+20+18+14+1, 35+33+20+18+14+2+1, 35+33+20+18+15+1, 35+33+20+18+15+2+1, 36+1, 37+1, 38+1, 39+1, 39+2+1, 39+3+1, 39+3+2+1, 39+5+1, 39+9+1, 39+9+2+1, 39+12+1, 39+13+1, 39+13+2+1, 39+14+1, 39+14+2+1, 39+35+33+1, 39+35+33+2+1, 39+35+33+3+1, 39+35+33+3+2+1, 39+35+33+4+1, 39+35+33+4+2+1, 39+35+33+9+1, 39+35+33+9+2+1, 39+35+33+10+1, 39+35+33+10+2+1, 39+35+33+11+1, 39+35+33+11+2+1, 39+35+33+12+1, 39+35+33+13+1, 39+35+33+13+2+1, 39+35+33+14+1, 39+35+33+14+2+1, 39+35+33+20+1, 39+35+33+20+2+1, 39+35+33+20+14+1, 39+35+33+20+14+2+1, 39+35+33+20+18+1, 39+35+33+20+18+2+1, 39+35+33+20+18+3+1, 39+35+33+20+18+3+2+1, 39+35+33+20+18+4+1, 39+35+33+20+18+4+2+1, 39+35+33+20+18+5+1, 39+35+33+20+18+9+1, 39+35+33+20+18+9+2+1, 39+35+33+20+18+10+1, 39+35+33+20+18+10+2+1, 39+35+33+20+18+12+1, 39+35+33+20+18+13+1, 39+35+33+20+18+13+2+1, 39+35+33+20+18+14+1, 39+35+33+20+18+14+2+1, 39+35+33+20+18+15+1, 39+35+33+20+18+15+2+1, 40+1, 41+1, 42+1, 43+1, 43+2+1, 43+3+1, 43+3+2+1, 43+4+1, 43+4+2+1, 43+5+1, 43+8+1, 43+9+1, 43+9+2+1, 43+12+1, 43+13+1, 43+13+2+1, 43+14+1, 43+14+2+1, 43+35+33+1, 43+35+33+2+1, 43+35+33+3+1, 43+35+33+3+2+1, 43+35+33+4+1, 43+35+33+4+2+1, 43+35+33+9+1, 43+35+33+9+2+1, 43+35+33+10+1, 43+35+33+10+2+1, 43+35+33+11+1, 43+35+33+11+2+1, 43+35+33+12+1, 43+35+33+13+1, 43+35+33+13+2+1, 43+35+33+14+1, 43+35+33+14+2+1, 43+35+33+20+1, 43+35+33+20+2+1, 43+35+33+20+14+1, 43+35+33+20+14+2+1, 43+35+33+20+18+1, 43+35+33+20+18+2+1, 43+35+33+20+18+3+1, 43+35+33+20+18+3+2+1, 43+35+33+20+18+4+1, 43+35+33+20+18+4+2+1, 43+35+33+20+18+5+1, 43+35+33+20+18+9+1, 43+35+33+20+18+9+2+1, 43+35+33+20+18+10+1, 43+35+33+20+18+10+2+1, 43+35+33+20+18+12+1, 43+35+33+20+18+13+1, 43+35+33+20+18+13+2+1, 43+35+33+20+18+14+1, 43+35+33+20+18+14+2+1, 43+35+33+20+18+15+1, 43+35+33+20+18+15+2+1, 44+1, 44+2+1, 44+3+1, 44+3+2+1, 44+4+1, 44+4+2+1, 44+5+1, 44+9+1, 44+9+2+1, 44+12+1, 44+13+1, 44+13+2+1, 44+14+1, 44+14+2+1, 45+1, 45+2+1, 45+3+1, 45+3+2+1, 45+5+1, 45+8+1, 45+12+1, 45+13+1, 45+13+2+1, 45+14+1, 45+14+2+1, 45+35+33+1, 45+35+33+2+1, 45+35+33+3+1, 45+35+33+3+2+1, 45+35+33+4+1, 45+35+33+4+2+1, 45+35+33+9+1, 45+35+33+9+2+1, 45+35+33+10+1, 45+35+33+10+2+1, 45+35+33+11+1, 45+35+33+11+2+1, 45+35+33+12+1, 45+35+33+13+1, 45+35+33+13+2+1, 45+35+33+14+1, 45+35+33+14+2+1, 45+35+33+20+1, 45+35+33+20+2+1, 45+35+33+20+14+1, 45+35+33+20+14+2+1, 45+35+33+20+18+1, 45+35+33+20+18+2+1, 45+35+33+20+18+3+1, 45+35+33+20+18+3+2+1, 45+35+33+20+18+4+1, 45+35+33+20+18+4+2+1, 45+35+33+20+18+5+1, 45+35+33+20+18+9+1, 45+35+33+20+18+9+2+1, 45+35+33+20+18+10+1, 45+35+33+20+18+10+2+1, 45+35+33+20+18+12+1, 45+35+33+20+18+13+1, 45+35+33+20+18+13+2+1, 45+35+33+20+18+14+1, 45+35+33+20+18+14+2+1, 45+35+33+20+18+15+1, 45+35+33+20+18+15+2+1, 46+1, 47+1, 48+1, 49+1, 50+1, 51+1, 51+2+1, 51+3+1, 51+3+2+1, 51+4+1, 51+4+2+1, 51+5+1, 51+7+1, 51+7+2+1, 51+8+1, 51+9+1, 51+9+2+1, 51+12+1, 51+13+1, 51+13+2+1, 51+14+1, 51+14+2+1, 52+1, 53+1, 53+2+1, 53+3+1, 53+3+2+1, 53+4+1, 53+4+2+1, 53+5+1, 53+6+1, 53+7+1, 53+7+2+1, 53+8+1, 53+9+1, 53+9+2+1, 53+10+1, 53+10+2+1, 53+11+1, 53+11+2+1, 53+12+1, 53+13+1, 53+13+2+1, 53+14+1, 53+14+2+1, 53+15+1, 53+15+2+1, 53+22+1, 53+22+2+1, 53+22+3+1, 53+22+3+2+1, 53+22+4+1, 53+22+4+2+1, 53+22+5+1, 53+22+6+1, 53+22+12+1, 53+22+13+1, 53+22+13+2+1, 53+22+14+1, 53+22+14+2+1, 53+22+15+1, 53+22+15+2+1, 53+22+18+1, 53+22+18+2+1, 53+22+18+3+1, 53+22+18+3+2+1, 53+22+18+4+1, 53+22+18+4+2+1, 53+22+18+5+1, 53+22+18+9+1, 53+22+18+9+2+1, 53+22+18+10+1, 53+22+18+10+2+1, 53+22+18+12+1, 53+22+18+13+1, 53+22+18+13+2+1, 53+22+18+14+1, 53+22+18+14+2+1, 53+22+18+15+1, 53+22+18+15+2+1, 53+22+20+1, 53+22+20+2+1, 53+22+20+14+1, 53+22+20+14+2+1, 53+22+20+18+1, 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53+23+20+18+10+2+1, 53+23+20+18+12+1, 53+23+20+18+13+1, 53+23+20+18+13+2+1, 53+23+20+18+14+1, 53+23+20+18+14+2+1, 53+23+20+18+15+1, 53+23+20+18+15+2+1, 53+43+1, 53+43+2+1, 53+43+3+1, 53+43+3+2+1, 53+43+4+1, 53+43+4+2+1, 53+43+5+1, 53+43+8+1, 53+43+9+1, 53+43+9+2+1, 53+43+12+1, 53+43+13+1, 53+43+13+2+1, 53+43+14+1, 53+43+14+2+1, 53+43+35+33+1, 53+43+35+33+2+1, 53+43+35+33+3+1, 53+43+35+33+3+2+1, 53+43+35+33+4+1, 53+43+35+33+4+2+1, 53+43+35+33+9+1, 53+43+35+33+9+2+1, 53+43+35+33+10+1, 53+43+35+33+10+2+1, 53+43+35+33+11+1, 53+43+35+33+11+2+1, 53+43+35+33+12+1, 53+43+35+33+13+1, 53+43+35+33+13+2+1, 53+43+35+33+14+1, 53+43+35+33+14+2+1, 53+43+35+33+20+1, 53+43+35+33+20+2+1, 53+43+35+33+20+14+1, 53+43+35+33+20+14+2+1, 53+43+35+33+20+18+1, 53+43+35+33+20+18+2+1, 53+43+35+33+20+18+3+1, 53+43+35+33+20+18+3+2+1, 53+43+35+33+20+18+4+1, 53+43+35+33+20+18+4+2+1, 53+43+35+33+20+18+5+1, 53+43+35+33+20+18+9+1, 53+43+35+33+20+18+9+2+1, 53+43+35+33+20+18+10+1, 53+43+35+33+20+18+10+2+1, 53+43+35+33+20+18+12+1, 53+43+35+33+20+18+13+1, 53+43+35+33+20+18+13+2+1, 53+43+35+33+20+18+14+1, 53+43+35+33+20+18+14+2+1, 53+43+35+33+20+18+15+1, 53+43+35+33+20+18+15+2+1, 54+1, 54+2+1, 54+3+1, 54+3+2+1, 54+4+1, 54+4+2+1, 54+5+1, 54+6+1, 54+7+1, 54+7+2+1, 54+8+1, 54+9+1, 54+9+2+1, 54+10+1, 54+10+2+1, 54+11+1, 54+11+2+1, 54+12+1, 54+13+1, 54+13+2+1, 54+14+1, 54+14+2+1, 54+15+1, 54+15+2+1, 54+22+1, 54+22+2+1, 54+22+3+1, 54+22+3+2+1, 54+22+4+1, 54+22+4+2+1, 54+22+5+1, 54+22+6+1, 54+22+12+1, 54+22+13+1, 54+22+13+2+1, 54+22+14+1, 54+22+14+2+1, 54+22+15+1, 54+22+15+2+1, 54+22+18+1, 54+22+18+2+1, 54+22+18+3+1, 54+22+18+3+2+1, 54+22+18+4+1, 54+22+18+4+2+1, 54+22+18+5+1, 54+22+18+9+1, 54+22+18+9+2+1, 54+22+18+10+1, 54+22+18+10+2+1, 54+22+18+12+1, 54+22+18+13+1, 54+22+18+13+2+1, 54+22+18+14+1, 54+22+18+14+2+1, 54+22+18+15+1, 54+22+18+15+2+1, 54+22+20+1, 54+22+20+2+1, 54+22+20+14+1, 54+22+20+14+2+1, 54+22+20+18+1, 54+22+20+18+2+1, 54+22+20+18+3+1, 54+22+20+18+3+2+1, 54+22+20+18+4+1, 54+22+20+18+4+2+1, 54+22+20+18+5+1, 54+22+20+18+9+1, 54+22+20+18+9+2+1, 54+22+20+18+10+1, 54+22+20+18+10+2+1, 54+22+20+18+12+1, 54+22+20+18+13+1, 54+22+20+18+13+2+1, 54+22+20+18+14+1, 54+22+20+18+14+2+1, 54+22+20+18+15+1, 54+22+20+18+15+2+1, 54+23+1, 54+23+2+1, 54+23+3+1, 54+23+3+2+1, 54+23+4+1, 54+23+4+2+1, 54+23+5+1, 54+23+6+1, 54+23+8+1, 54+23+9+1, 54+23+9+2+1, 54+23+10+1, 54+23+10+2+1, 54+23+11+1, 54+23+11+2+1, 54+23+18+1, 54+23+18+2+1, 54+23+18+3+1, 54+23+18+3+2+1, 54+23+18+4+1, 54+23+18+4+2+1, 54+23+18+5+1, 54+23+18+9+1, 54+23+18+9+2+1, 54+23+18+10+1, 54+23+18+10+2+1, 54+23+18+12+1, 54+23+18+13+1, 54+23+18+13+2+1, 54+23+18+14+1, 54+23+18+14+2+1, 54+23+18+15+1, 54+23+18+15+2+1, 54+23+20+1, 54+23+20+2+1, 54+23+20+14+1, 54+23+20+14+2+1, 54+23+20+18+1, 54+23+20+18+2+1, 54+23+20+18+3+1, 54+23+20+18+3+2+1, 54+23+20+18+4+1, 54+23+20+18+4+2+1, 54+23+20+18+5+1, 54+23+20+18+9+1, 54+23+20+18+9+2+1, 54+23+20+18+10+1, 54+23+20+18+10+2+1, 54+23+20+18+12+1, 54+23+20+18+13+1, 54+23+20+18+13+2+1, 54+23+20+18+14+1, 54+23+20+18+14+2+1, 54+23+20+18+15+1, 54+23+20+18+15+2+1, 54+43+1, 54+43+2+1, 54+43+3+1, 54+43+3+2+1, 54+43+4+1, 54+43+4+2+1, 54+43+5+1, 54+43+8+1, 54+43+9+1, 54+43+9+2+1, 54+43+12+1, 54+43+13+1, 54+43+13+2+1, 54+43+14+1, 54+43+14+2+1, 54+43+35+33+1, 54+43+35+33+2+1, 54+43+35+33+3+1, 54+43+35+33+3+2+1, 54+43+35+33+4+1, 54+43+35+33+4+2+1, 54+43+35+33+9+1, 54+43+35+33+9+2+1, 54+43+35+33+10+1, 54+43+35+33+10+2+1, 54+43+35+33+11+1, 54+43+35+33+11+2+1, 54+43+35+33+12+1, 54+43+35+33+13+1, 54+43+35+33+13+2+1, 54+43+35+33+14+1, 54+43+35+33+14+2+1, 54+43+35+33+20+1, 54+43+35+33+20+2+1, 54+43+35+33+20+14+1, 54+43+35+33+20+14+2+1, 54+43+35+33+20+18+1, 54+43+35+33+20+18+2+1, 54+43+35+33+20+18+3+1, 54+43+35+33+20+18+3+2+1, 54+43+35+33+20+18+4+1, 54+43+35+33+20+18+4+2+1, 54+43+35+33+20+18+5+1, 54+43+35+33+20+18+9+1, 54+43+35+33+20+18+9+2+1, 54+43+35+33+20+18+10+1, 54+43+35+33+20+18+10+2+1, 54+43+35+33+20+18+12+1, 54+43+35+33+20+18+13+1, 54+43+35+33+20+18+13+2+1, 54+43+35+33+20+18+14+1, 54+43+35+33+20+18+14+2+1, 54+43+35+33+20+18+15+1, 54+43+35+33+20+18+15+2+1, 54+44+1, 54+44+2+1, 54+44+3+1, 54+44+3+2+1, 54+44+4+1, 54+44+4+2+1, 54+44+5+1, 54+44+9+1, 54+44+9+2+1, 54+44+12+1, 54+44+13+1, 54+44+13+2+1, 54+44+14+1, 54+44+14+2+1, 54+45+1, 54+45+2+1, 54+45+3+1, 54+45+3+2+1, 54+45+5+1, 54+45+8+1, 54+45+12+1, 54+45+13+1, 54+45+13+2+1, 54+45+14+1, 54+45+14+2+1, 54+45+35+33+1, 54+45+35+33+2+1, 54+45+35+33+3+1, 54+45+35+33+3+2+1, 54+45+35+33+4+1, 54+45+35+33+4+2+1, 54+45+35+33+9+1, 54+45+35+33+9+2+1, 54+45+35+33+10+1, 54+45+35+33+10+2+1, 54+45+35+33+11+1, 54+45+35+33+11+2+1, 54+45+35+33+12+1, 54+45+35+33+13+1, 54+45+35+33+13+2+1, 54+45+35+33+14+1, 54+45+35+33+14+2+1, 54+45+35+33+20+1, 54+45+35+33+20+2+1, 54+45+35+33+20+14+1, 54+45+35+33+20+14+2+1, 54+45+35+33+20+18+1, 54+45+35+33+20+18+2+1, 54+45+35+33+20+18+3+1, 54+45+35+33+20+18+3+2+1, 54+45+35+33+20+18+4+1, 54+45+35+33+20+18+4+2+1, 54+45+35+33+20+18+5+1, 54+45+35+33+20+18+9+1, 54+45+35+33+20+18+9+2+1, 54+45+35+33+20+18+10+1, 54+45+35+33+20+18+10+2+1, 54+45+35+33+20+18+12+1, 54+45+35+33+20+18+13+1, 54+45+35+33+20+18+13+2+1, 54+45+35+33+20+18+14+1, 54+45+35+33+20+18+14+2+1, 54+45+35+33+20+18+15+1, 54+45+35+33+20+18+15+2+1, 55+1, 56+1;

wherein the list above is not to be construed as limiting with respect to further embodiments which are also possible based on the dependencies of the embodiments 1) to 56) as disclosed hereinabove and which are also intended. In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “9+2+1” for example refers to embodiment 9) depending on embodiment 2) depending on embodiment 1), i.e. embodiment “9+2+1” corresponds to embodiment 1) further limited by the features of embodiments 2) and 9).

Unless explicitly stated otherwise, the general terms and names used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings: Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, pharmaceutical composition, disease or the like.

The term “pharmaceutically acceptable salts” refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.

The compounds of formula (I) according to any one of embodiments 1) to 56), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.

In a preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 56), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of asthma, allergic asthma, eosinophilic asthma, severe asthma, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria and eczema.

In another preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 56), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).

In yet another preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 56), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.

In a more preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 56), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of asthma, allergic asthma, eosinophilic asthma, severe asthma and allergic rhinitis.

In another more preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 56), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of eosinophilic esophagitis.

In still another more preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 56), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of atopic dermatitis.

The invention also relates to the use of a compound of formula (I) according to any one of embodiments 1) to 56) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.

The present invention also relates to pharmaceutically acceptable salts and to pharmaceutical compositions and formulations of compounds of formula (I) according to any one of embodiments 1) to 56).

A pharmaceutical composition according to the present invention contains at least one compound of formula (I) according to any one of embodiments 1) to 56) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.

The compounds of formula (I) according to any one of embodiments 1) to 56) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such as especially oral) or parenteral (including topical application or inhalation) administration.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to any one of embodiments 1) to 56), or a pharmaceutically acceptable salt thereof.

The present invention also includes isotopically labelled, especially ²H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ²H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope ²H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

Any reference to a compound of formula (I), (I_(P)), (I_(St1)), (I_(St2)), (I-1) or (I-2) in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The preferences indicated for the compounds of formula (I) of course apply mutatis mutandis to the compounds of formula (I_(P)), the compounds of formula (I_(St1)), the compounds of formula (I_(St2)), the compounds of formula (I-1) and the compounds of formula (I-2) as well as to the salts and pharmaceutically acceptable salts of the compounds of formula (I), of formula (I_(P)), of formula (I_(St1)), of formula (I_(St2)), of formula (I-1) and of formula (I-2). The same applies to these compounds as medicaments, to pharmaceutical compositions containing these compounds as active principles or to the uses of these compounds for the manufacture of a medicament for the treatment of the diseases according to this invention.

Unless used regarding temperatures, the term “about” (or alternatively “around”) placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” (or alternatively “around”) placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10° C. to Y plus 10° C., and preferably to an interval extending from Y minus 5° C. to Y plus 5° C. Besides, the term “room temperature” (r.t.) as used herein refers to a temperature of about 25° C.

Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40° C. and 80° C., this means that the end points 40° C. and 80° C. are included in the range or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.

As mentioned earlier, compounds of formula (I) modulate the PGD₂ activation of the CRTH2 receptor. The biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays. The ability of the compounds of formula (I) to bind to the CRTH2 receptor may be measured by methods similar to those described in the literature (Arimura A. et al., J. Pharmacol. Exp. Ther. 2001, 298(2), 411-419; and Sawyer N. et al., Br. J. Pharmacol, 2002, 137, 1163-1172, respectively) and by the assays described below in the experimental part.

A further aspect of the invention is a process for the preparation of compounds of Formula (I). Compounds according to Formula (I) of the present invention can be prepared according to the sequence of reactions outlined in the schemes below wherein Z, n, m, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined for Formula (I). Other abbreviations used are defined in the experimental section. In some instances the generic groups Z, n, m, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ might be incompatible with the assembly illustrated in the schemes below and, therefore, will require the use of protecting groups (PG). For example it may be necessary to protect reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). It will be assumed that such protecting groups are as necessary in place. In the following description, for example, “PG”, when used as amino-protecting group, preferably refers to a group such as tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl or benzyl, most preferably benzyloxycarbonyl. Further, “L” refers to a leaving group, such as an activated hydroxy group (for examples as mesylate, tosylate, active ester etc.), an in-situ activated hydroxy group (as used, for instance, in Mitsunobu reactions), or a halogen, in particular chloro or bromo. Further, “R” refers to a (C₁-C₄)alkyl group, preferably methyl, ethyl or tert-butyl.

In general, all chemical transformations can be performed according to well-known standard methodologies as described in the literature or as described in the procedures below. The compounds obtained may also be converted into pharmaceutically acceptable salts thereof in a manner known per se.

Generally, compounds of Formula (I) (or of Formula (I_(P))), are obtained from an ester of Structure 1, wherein one of R^(A), R^(B) and R^(C) represents (C₁-C₄)alkoxy-carbonyl-cyclopropyl, (C₁-C₄)alkoxy-carbonyl-(C₁-C₃)alkyl or (C₁-C₄)alkoxy-carbonyl-(C₁-C₃)alkoxy and the other two represent independently of each other hydrogen, (C₁-C₄)alkoxy or halogen, by hydrolysis of the ester group using routine procedures. For example, a methyl- or ethyl-ester derivative of Structure 1 can be saponified with an aqueous solution of LiOH, NaOH, or KOH in an organic co-solvent such as an alcohol (like MeOH or EtOH), THF, acetone, MeCN, or DMF; alternatively a tert.-butyl-ester derivative of Structure 1 can be cleaved with an acid like TFA.

An intermediate of Structure 1 is for instance obtained by reacting an intermediate of Structure 2, or a salt thereof, such as a hydrochloride salt, with a reagent of Formula L-C(O)Z—R⁸, wherein Z and R⁸ are as defined for Formula (I) (or for Formula (I_(P))) and L is a leaving group such as an halogen (in particular chloro), in the presence of a base like NEt₃, DIPEA, N-ethyl-morpholine, N-methylpiperidine, or pyridine, in a suitable solvent, such as THF, or DCM. The starting material L-C(O)Z—R⁸ may be a chloroformate; an acyl anhydride; or an acyl halide like an acid chloride or an acid bromide. The acyl halide may be commercially available, known in the art or obtainable in situ from the corresponding commercially available or well known carboxylic acid in a reaction with a halogenating reagent like oxalyl chloride or phosphorous oxychloride under conditions known to a skilled person.

In another aspect, an intermediate of Structure 2 is reacted with a commercially available or well known isocyanate in the presence of a base like NEt₃ or DIPEA to form an intermediate of Structure 1.

In a further aspect, an intermediate of Structure 2 is condensed with a commercially available or well known carboxylic acid in the presence of a coupling reagent, such as EDC, TBTU, diisopropylcarbodiimide, HATU, DCC, Ghosez's reagent or the like, in the presence of a base like NEt₃, DIPEA, or pyridine to form an intermediate of Structure 1.

In another aspect an intermediate of Structure 2 is reacted with a carbonate 3, wherein R^(D) represents optionally substituted aryl, in the presence of a base like NEt₃ or DIPEA to give an intermediate of Structure 1-A (Scheme 1). A carbonate 3 is prepared by reaction of a benzyl alcohol 4 with N,N′-disuccinimidyl carbonate in the presence of a base like DMAP.

Alternatively an intermediate of Structure 2 is condensed with 4-nitrophenyl chloroformate in the presence of a base like NEt₃ or DIPEA to give a carbamate 5 (Scheme 2). The carbamate 5 is then treated with an alcohol R^(E)OH, wherein R^(E) represents (C₂-C₅)alkyl; (C₁-C₅)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; (C₃-C₅)alkenyl; or (C₃-C₅)alkynyl in the presence of potassium tert-butoxide to give a compound of Formula (I-A). Under these specific conditions, the saponification of the ester group of R^(A), R^(B), or R^(C) and the substitution take place during the same reaction.

An intermediate of Structure 2 is obtained after removal of a protecting group (PG) from an intermediate of Structure 6, applying reaction conditions known to a skilled person. Preferably, PG is a group such as tert-butoxycarbonyl or benzyloxycarbonyl. A benzyloxycarbonyl protecting group is removed by hydrogenolysis or treatment with an acid; a tert-butoxycarbonyl group is cleaved under acidic conditions. PG can also be a benzyl protecting group, which can be cleaved by hydrogenolysis.

An intermediate of Structure 6 is obtained by one of the synthetic pathways described below. For example, an intermediate of Structure 6 is obtained via Suzuki cross-coupling reaction between a compound of Structure 7, wherein R^(F) represents bromo, chloro, or triflate and a boronic acid or boronic ester derivative 8, wherein R^(G) represents hydroxy or pinacol in the presence of a base like Na₂CO₃ or K₃PO₄, and a palladium catalyst like Pd(PPh₃)₄, or Pd(OAc)₂ and (S)-Phos (Scheme 3). If not commercially available, the boronic ester derivatives 8 can be obtained from the corresponding compounds 9, wherein R^(H) represents chloro, bromo or triflate (preferably bromo) by treatment with bis(pinacolato)diboron 10 in the presence of a base like potassium acetate and a palladium catalyst like Pd(PPh₃)₄ or Pd(dppf)Cl₂. Alternatively, a compound of Structure 7 can be converted in a boronic ester derivative 11 by treatment with bis(pinacolato)diboron 10 in the presence of a base like potassium acetate and a palladium catalyst like Pd(PPh₃)₄ or Pd(dppf)Cl₂. The resulting boronic ester 11 can undergo a Suzuki cross-coupling reaction with compound 9, wherein R^(H) represents chloro, bromo or triflate (preferably bromo) in the presence of a base like Na₂CO₃ or K₃PO₄, and a palladium catalyst like Pd(PPh₃)₄, or Pd(OAc)₂ and (S)-Phos to give a compound of Structure 6.

Alternatively, a compound of Structure 7 can be reacted in a Suzuki cross-coupling reaction with a boronic acid 12, wherein one of R^(I), R^(J) and R^(K) represents hydroxy and the other two represent independently of each other hydrogen, (C₁-C₄)alkoxy or halogen, in the presence of a base like Na₂CO₃ or K₃PO₄, and a palladium catalyst like Pd(PPh₃)₄, or Pd(OAc)₂ and (S)-Phos. The resulting phenol 13 can then be alkylated with an electrophile L-(C₁-C₃)alkyl-CO₂R, wherein R represents (C₁-C₄)alkyl and L is a leaving group such as bromide or tosyl which is attached to any carbon atom of the (C₁-C₃)alkyl group, in the presence of a base like Cs₂CO₃ or K₂CO₃ to give an intermediate of Structure 6-A (Scheme 4).

In another aspect, a compound of Structure 2-A, wherein n represents 1 and m represents 2 (a tetrahydroisoquinoline) can be obtained by catalytic hydrogenation of an isoquinoline 14 in the presence of a platinum catalyst under an hydrogen atmosphere (Scheme 5). An isoquinoline 14 is obtained by a Suzuki cross-coupling reaction between an isoquinoline 15 and a boronic acid or boronic ester 8 in the presence of a base like Na₂CO₃ or K₃PO₄, and a palladium catalyst like Pd(PPh₃)₄, or Pd(OAc)₂ and (S)-Phos.

An intermediate of Structure 7, wherein n represents 1 and m represents 2 or n represents 2 and m represents 1 (a tetrahydroisoquinoline) is obtained by one of the synthetic pathways described below (Schemes 6 to 9). For example, a 3,4-dihydroisoquinoline 16, wherein R^(L) represents chloro or bromo, can be reduced using for example NaBH₄ to afford the tetrahydroisoquinoline 17, which can be treated with a protecting group precursor PGL such as di-tert-butyl dicarbonate or a chloroformate (like benzyl chloroformate) in the presence of a base like NEt₃ or DIPEA to give a compound of Structure 7-A. The required 3,4-dihydroisoquinolines 16, are prepared from the corresponding phenethylamines 18 (or the corresponding hydrochloride salts) using a modified Bischler-Napieralski reaction. Thus, reaction of a phenethylamine 18 with ethyl formiate affords the corresponding formamide, which is transformed into an oxazolo intermediate upon treatment with oxalyl chloride and iron(III) chloride. Treatment of the oxazolo derivative with methanol in the presence of an acid like sulphuric acid yields the desired 3,4-dihydroisoquinoline 16. If not commercially available, the phenethylamines 18 may be synthesized by reduction of the corresponding α,β-unsaturated nitro derivatives 19, which are prepared from the aldehydes 20 via an Henry reaction (Scheme 6).

Alternatively, a phenethylamine 21, prepared from the corresponding aldehyde 22 following the sequence depicted in Scheme 6, is transformed into a formamide, which is then heated in a strong acid like PPA to give the 3,4-dihydroisoquinoline 23 (Scheme 7). Compound 23 can then be demethylated in the presence of aluminum trichloride, followed by reduction with NaBH₄ and treatment with a protecting group precursor PGL such as di-tert-butyl dicarbonate or a chloroformate (like benzyl chloroformate) in the presence of a base like NEt₃ or DIPEA to give a tetrahydroisoquinoline 24. Upon treatment with zinc cyanide in the presence of a palladium catalyst and poly(methylhydrosiloxane), the bromide 24 can be transformed into a nitrile, which can then be transformed into a triflate of Structure 7-B upon treatment with trifluoromethanesulfonic anhydride in the presence of a base like NEt₃.

In another aspect, a bromide 25, prepared following the synthetic sequence depicted in Scheme 6, can be transformed in the corresponding sulfone of Structure 7-C using the sulfinate derivative MeS(O)ONa in the presence of a copper catalyst like CuI and a ligand like prolinate (Scheme 8).

Following the synthetic pathway depicted in Scheme 6, but starting from the corresponding aldehyde 26 an intermediate of Structure 7-D, wherein n represents 2 and m represents 1 (a tetrahydroisoquinoline) can be prepared (Scheme 9).

An intermediate of Structure 7-E, wherein n represents 1 and m represents 1 (an isoindoline) can be obtained by the synthetic pathway described in Scheme 10. Thus a dimethylbenzene derivative 27, wherein R^(M) represents bromo or chloro, is brominated with for example NBS in the presence of a radical initiator like benzoyl peroxide to give the dibromide 28. The dibromide 28 can then react with a protected primary amine, like benzylamine, in the presence of a base like potassium carbonate, to give an isoindoline of Structure 7-E, wherein PG represents benzyl.

An intermediate of Structure 7-F, wherein n represents 2 and m represents 2 (a benzazepine) can be obtained by the synthetic pathway described below (Scheme 11). Thus a phenethylamine 29, prepared following the sequence depicted in Scheme 6, undergoes a condensation with glyoxal dimethyl acetal in a solvent like MeOH. The resulting imine is then reduced in the presence of NaBH₄ to give the amine 30. Protection of the amine 30 with trifluoroacetic anhydride, TFA mediated cyclization, and subsequent catalytic hydrogenation lead to the benzazepine 31. Demethylation using for example BBr₃ followed by cleavage of the trifluoroacetamide moiety with a base like NaOH gives the benzazepine 32, which can be treated with a protecting group precursor PGL such as di-tert-butyl dicarbonate or a chloroformate like benzyl chloroformate in the presence of a base like NEt₃ or DIPEA to give the benzazepine 33. The resulting phenol 33 can be converted into a triflate of Structure 7-F by treatment with trifluoromethanesulfonic anhydride in the presence of a base like NEt₃.

The isoquinolines 15 are prepared as described in Scheme 12. The aldehydes 34, wherein R^(N) represents bromo, chloro, or methoxy, undergo a reductive amination with the amine 35 to give the secondary amine 36, which can be converted with tosyl chloride into a sulfonamide 37 in the presence of a base like NEt₃. In case R^(N) represents bromo or chloro, the sulfonamide 37 is converted into the isoquinoline 15-A by treatment with aluminum trichloride. In case R^(N) represents methoxy, an isoquinoline 38 is obtained by treatment of 37 with aluminum trichloride. The isoquinoline 38 is then converted into the triflate 15-B upon treatment with trifluoromethanesulfonic anhydride in the presence of a base like NEt₃.

If not commercially available, halogenated derivatives 9-A wherein R^(O) represents chloro or bromo can be prepared from the corresponding benzoic acid 39, wherein one of R^(P), R^(Q) and R^(R) represents carboxy and the other two represent independently of each other hydrogen, (C₁-C₄)alkoxy or halogen, via an Arndt-Eistert homologation. The benzoic acid derivatives 39 are first converted into acyl chlorides, for example by treatment with oxalyl chloride in the presence of a catalytic amount of DMF (Scheme 13). The resulting acyl chlorides are then converted into diazoethanone derivatives upon treatment with trimethylsilyl diazomethane. The diazoethanone derivatives can then undergo a Wolff rearrangement in the presence of an alcohol like EtOH, a base like NEt₃, and a silver salt like silver benzoate to give the halogenated compounds 9-A, wherein one of R^(A), R^(B) or R^(C) represents the respective alkoxy-carbonyl-methyl moiety.

Alternatively, halogenated derivatives 9-B can be prepared by alkylation of phenols 40, wherein one of R^(S), R^(T) and R^(U) represents hydroxy and the other two represent independently of each other hydrogen, (C₁-C₄)alkoxy or halogen, with an electrophile L-(C₁-C₃)alkyl-CO₂R, wherein R represents (C₁-C₄)alkyl and L is a leaving group such as bromide or tosyl which is attached to any carbon atom of the (C₁-C₃)alkyl group, in the presence of a base like Cs₂CO₃ or K₂CO₃ (Scheme 14).

In another aspect, a compound 9-C can be prepared by alkylation of a phenol 41 with L-R^(V), wherein L represents a leaving group like iodide, bromide, chloride or triflate and R^(V) represents (C₁-C₄)alkyl, (C₁-C₄)fluoroalkyl, or methoxy-ethyl in the presence of a base like potassium carbonate (Scheme 15). In analogy, alkylation of both, the hydroxy and the carboxy group of phenol 42 with L-R^(V) in the presence of a base like potassium carbonate and subsequent saponification of the obtained ester with an aqueous solution of NaOH, KOH, or LiOH in the presence of a co-solvent like THF or EtOH gives a benzoic acid 39-A. Alternatively, the acid 42 may be selectively esterified by, for example, treatment with HCl in a solvent like EtOH. The resulting phenol can then be alkylated with L-R^(V) in the presence of a base like potassium carbonate. A final saponification with an aqueous solution of NaOH, KOH, or LiOH in the presence of a co-solvent like THF or EtOH yields a benzoic acid 39-A.

Acid derivatives used in the amide coupling with compounds of Structure 2 are commercially available, known in the art, or obtainable according to Schemes 16, 17, 18 or 19. A cinnamic acid 43, wherein R^(W) and R^(X) independently represent hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, or halogen, is converted to the Weinreb amide 44 using standard amide coupling conditions such as EDC in the presence of a base like DMAP in a solvent like DMF. Corey-Chaykovsky cyclopropanation gives the cyclopropane (±)-45, which is hydrolyzed to the corresponding carboxylic acid (±)-46 with a base like potassium tert-butoxide (Scheme 16).

Optically pure phenylcyclopropyl carboxylic acid (R,R)-47 can be prepared following the synthetic sequence depicted in Scheme 17. A styrene derivative 48, wherein R^(W) and R^(X) independently represent hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, or halogen, is converted into epoxide (S)-49 via Sharpless-dihydroxylation using AD-mix-α (J. Org. Chem. 1992, 57, 2768-2771), followed by transformation of the resulting diol into the respective epoxide using a protocol developed by Sharpless et al. (Tetrahedron 1992, 48, 10515-10530). The epoxide (S)-49 undergoes an Horner-Emmons cyclopropanation in the presence of triethyl phosphonoacetate and a base like nBuLi to give the ester (R,R)-50, which is hydrolyzed to the corresponding phenylcyclopropyl carboxylic acid (R,R)-47 (Scheme 17).

Pyridine carboxylic acid (±)-52 can be prepared following the synthetic Scheme 18. An Horner-Emmons olefination between a pyridine derivative 53 (wherein R^(Y) represents hydrogen, (C₁-C₃)alkyl or (C₃-C₆)cycloalkyl, and R^(z) and R^(AA) independently represent hydrogen, halogen, (C₁-C₃)alkyl or (C₁-C₂)alkoxy) and dimethyl(benzyloxycarbonyl)methyl phosphonate, in the presence of a base like NaH, gives the α,β-unsaturated ester 54. The cis- and trans-isomer may be separated by column chromatography or may be used as a mixture in the next catalytic hydrogenation. Thus, upon treatment with Pd/C under an H₂-atmosphere in a solvent like THF, the α,β-unsaturated ester 54 is transformed into the racemic carboxylic acid (±)-52 (Scheme 18). In analogy, starting from a substituted pyridine anneleted to a cyclohexanone, like for example 6,7-dihydro-5H-quinolin-8-one, the corresponding carboxylic acid derivative, like for example (±)-2-(5,6,7,8-tetrahydroquinolin-8-yl)acetic acid, may be obtained.

The synthesis of carboxylic acid derivatives (±)-55 is depicted in Scheme 19. An Homer-Emmons olefination between a ketone 56 (wherein R^(AB) and R^(AC) independently represent hydrogen or halogen, one of Q and T represents —O— or —CH₂— and the other one is absent or represents —CH₂— or —C(Me)₂-) and a phosphonoacetate, like triethyl phosphonoacetate, in the presence of a base like NaH affords the α,β-unsaturated ester 57. The cis- and trans-isomer may be separated by column chromatography or may be used as a mixture in the next catalytic hydrogenation. The racemic acid (±)-55 is obtained through catalytic hydrogenation of the α,β-unsaturated ester 57 in the presence of Pd/C under an H₂-atmosphere in a solvent like EtOH and a subsequent ester hydrolysis with an aqueous solution of NaOH in a co-solvent like THF or EtOH (Scheme 19).

Whenever the compounds of Formula (I) are obtained in the form of mixtures of enantiomers or diastereoisomers, the enantiomers or diastereoisomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a ChiralPak AD-H (5 μm) column, ChiralPak AY-H (5 μm) column, a ChiralPak IA (5 μm) column, a ChiralPak IB (5 μm) column, or a Regis (R,R)-Whelk-01 (5 μm). Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH or DCM, in presence or absence of a base like NEt₃ and/or diethylamine or of an acid like TFA) and eluent B (heptane).

EXPERIMENTAL SECTION Abbreviations (as Used Herein)

-   AcOEt Ethyl acetate -   AcOH Acetic acid -   aq. aqueous -   Bdg Binding -   BSA Bovine Serum Albumin -   Bu n-butyl -   ca. circa (latin)—approximately -   Cbz Benzyloxycarbonyl -   CC Column chromatography on silica gel -   CDI Carbonyldiimidazole -   comb. combined -   conc. Concentrated -   dba Dibenzylidenaceton -   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene -   DCC 1,3-Dicyclohexylcarbodiimide -   DCM Dichloromethane -   DIPEA N,N-Diisopropylethylamine -   DMAC Dimethylacetamide -   DMAP N,N-Dimethyl-4-aminopyridine -   DME 1,2-Dimethoxyethane -   DMF Dimethylformamide -   DMSO Dimethylsulfoxide -   dpm decays per minute -   DPPF 1,1′-Bis(diphenylphosphino)ferrocen -   EDTA Ethylene Diamine Tetraacetic Acid -   EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide -   ee enantiomeric excess -   eq. Equivalent -   EtOH ethanol -   ESI-MS Electrospray Ionization Mass Spectroscopy -   Ghosez's reagent 1-Chloro-N,N,2-trimethyl-1-propenylamine -   h hour(s) -   HATU O-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium     hexafluorophosphate -   Hept Heptane -   HPLC High Performance Liquid Chromatography -   HSA human serum albumin -   h.v. high vacuum -   iPr isopropyl -   L liter(s) -   LAH lithium aluminum hydride -   LC-MS Liquid Chromatography-Mass Spectroscopy -   M molarity [mol L⁻¹] -   Me Methyl -   MeCN Acetonitrile -   MeI Methyl iodide -   MeOH Methanol -   mesyl Methanesulfonyl -   Meth. Method -   min minute(s) -   MS Mass Spectroscopy or Molecular Sieves -   MW Molecular Weight -   N Normality of solution -   NBS N-bromo-succinimide -   NEt₃ Triethylamine -   NMR Nuclear magnetic resonance -   org. organic -   PBS Phosphate Buffered Saline -   PG Protecting Group -   Ph Phenyl -   PGD₂ Prostaglandin D₂ -   (S)-Phos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl -   PMSF Phenylmethylsulfonyl fluoride -   PPA Polyphosphoric acid -   prep. preparative -   r.t. room temperature -   s second(s) -   sat. saturated -   Si-carbonate Polymer supported carbonate -   Si-DEA Polymer supported diethyl amine -   soln. solution -   subst. Substituted -   TBTU O-(Benzotriazol-1-yl)-N,N,N,N′-tetramethyluronium -   tBu tert-Butyl -   tert. Tertiary -   Tf Triflate -   TFA Trifluoroacetic acid -   TFAA Trifluoroacetic anhydride -   THF Tetrahydrofuran -   TMS Trimethylsilyl -   tosyl Toluenesulfonyl -   t_(R) retention time -   Tris Tris-(hydroxymethyl)aminomethane buffer -   Ts Tosyl

Chemistry

General Remarks

All solvents and reagents are used as obtained from commercial sources unless otherwise indicated.

Temperatures are indicated in degrees Celsius (° C.). Unless otherwise indicated, the reactions take place at room temperature (r.t.).

In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume relations (v/v), unless indicated otherwise.

Analytical HPLC conditions as used in the Examples below:

LC-MS 1

LC-MS-conditions: Analytical. Pump: Waters Acquity Binary Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: Acquity UPLC BEH C18 1.7 mm 2.1×50 mm ID from Waters, thermostated in the Acquity UPLC Column Manager at 60° C. Eluents: A: H₂O+0.05% formic acid or TFA; B: MeCN+0.05% formic acid or TFA. Method: Gradient: 2% B to 98% B over 2.00 min. Flow: 1.2 mL/min. Detection: UV/Vis and/or ELSD, and MS, t_(R) is given in min

LC-MS 1 FA: Eluents: A: H₂O+0.05% formic acid; B: MeCN+0.045% formic acid

LC-MS 1TFA: Eluents: A: H₂O+0.05% TFA; B: MeCN+0.045% TFA

LC-MS 2 to LC-MS 4

HPLC/MS analyses are performed on a Ultimate 3000RS Dionex HPLC instrument, equipped with a Dionex Ultimate 3000 RS Photodiode Array Detector, a Dionex Ultimate 3000RS pump and a Dionex MSQ⁺ mass spectrometer.

The LC retention times are obtained using the following elution conditions:

-   -   LC-MS 2: Analytical HPLC on a Waters X-Bridge C18 column (4.6×30         mm, 2.5 μm, Waters); Linear gradient of water/0.04% TFA (A) and         MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,         detection at 215 nm.     -   LC-MS 3: Analytical HPLC on a Zorbax® SB-AQ column (4.6×50 mm,         3.5 μm, Agilent); Linear gradient of water/0.04% TFA (A) and         MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,         detection at 215 nm.     -   LC-MS 4: Analytical HPLC on a Waters Atlantis T3 column (4.6×30         mm, 5 μm, Waters); Linear gradient of water/0.04% TFA (A) and         MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,         detection at 215 nm.

LC-MS 5 to LC-MS 12 (Chiral Analysis)

-   -   LC-MS 5: Analytical HPLC, column ChiralPak AD-H (4.6×250 mm, 5         μm), eluent A 80% Heptane and eluent B 20% EtOH+0.1% TFA, flow         0.8 mL/min. Detection at 210 nm.     -   LC-MS 6: Analytical HPLC, column ChiralPak AD-H (4.6×250 mm, 5         μm), eluent A 50% Heptane and eluent B 50% EtOH+0.1% TFA, flow         0.8 mL/min. Detection at 210 nm.     -   LC-MS 7: Analytical HPLC, column (R,R) Whelk-01 (4.6×250 mm, 5         μm), eluent A 70% Heptane and eluent B 30% EtOH+0.1% TFA, flow         1.6 mL/min. Detection at 210 nm.     -   LC-MS 8: Analytical HPLC, column (R,R) Whelk-01 (4.6×250 mm, 5         μm), eluent A 50% Heptane and eluent B 50% EtOH+0.1% TFA, flow         0.8 mL/min. Detection at 210 nm.     -   LC-MS 9: Analytical HPLC, column ChiralPak AS-H (4.6×250 mm, 5         μm), eluent A 80% Heptane and eluent B 20% EtOH+0.1% TFA, flow         1.0 mL/min. Detection at 210 nm.     -   LC-MS 10: Analytical HPLC, column ChiralPak AY-H (4.6×250 mm, 5         μm), eluent A 80% Heptane and eluent B 20% EtOH+0.1% TFA, flow         1.0 mL/min. Detection at 210 nm.     -   LC-MS 11: Analytical HPLC, column (R,R) Whelk-01 (4.6×250 mm, 5         μm), eluent A 80% Heptane and eluent B 20% EtOH+0.1% TFA, flow         0.8 mL/min. Detection at 210 nm.     -   LC-MS 12: Analytical HPLC, column ChiralPak IC (4.6×250 mm, 5         μm), eluent A 95% Heptane and eluent B 5% EtOH+0.1% TFA, flow         1.0 mL/min. Detection at 210 nm.

LC-MS 13

Analytical HPLC on a Supelco Ascentis Express C18 column (5×2.1 mm, 2.7 μm, Supelco); Linear gradient of water/0.05% formic acid (A) and MeCN (B) from 5% to 95% B over 2.5 min; flow rate 1.8 mL/min, detection at 214 and 254 nm.

Preparative HPLC/MS purifications are performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Finnigan AQA MS detector system, and a Dionex UV detector, using a Waters Xbridge C18 or an Waters Atlantis T3 column, with a linear gradient of water/formic acid 0.02% (A) and MeCN (B) (acidic conditions) or water/ammonia 0.02% (A) and MeCN (B) (basic conditions).

Synthesis of Compounds of Formula (I):

The following examples illustrate the preparation of compounds of the invention but do not at all limit the scope thereof. Whenever used in the experimental part, generic Structures 1, 2, 3 etc. Refer to the respective Structures described in preceeding general description of the preparation of compounds of Formula (I).

General Method for the Preparation of Compounds of Formula (I):

Saponification

To a solution of (±)-(3-{5-fluoro-2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid ethyl ester in DMF (1 mL), 2M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (ca. 1 mL), purified by prep. HPLC (column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 1 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 1 as starting material.

TABLE 1 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 1 (±)-(3-{5-Fluoro-2-[trans-2-(4-fluoro- C28H25NO4F2 1.04 478.3 phenyl)-cyclopropanecarbonyl]-1,2,3,4- 477.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 2 (±)-(3-{2-[trans-2-(4-Chloro-phenyl)- C28H25NO4ClF 1.10 494.3 cyclopropanecarbonyl]-5-fluoro-1,2,3,4- 493.15 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 3 (±)-(3-{2-[trans-2-(2-Chloro-phenyl)- C28H25NO4ClF 1.07 494.3 cyclopropanecarbonyl]-5-fluoro-1,2,3,4- 493.15 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 4 (±)-(3-{2-[trans-2-(3-Chloro-phenyl)- C28H25NO4ClF 1.10 494.3 cyclopropanecarbonyl]-5-fluoro-1,2,3,4- 493.15 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 5 (±)-(3-{5-Fluoro-2-[trans-2-(2-fluoro- C28H25NO4F2 1.04 478.3 phenyl)-cyclopropanecarbonyl]-1,2,3,4- 477.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 6 (±)-{3-[5-Fluoro-2-(trans-2-o-tolyl- C29H28NO4F 1.08 474.4 cyclopropanecarbonyl)-1,2,3,4- 473.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 7 8-(5-Carboxymethyl-2-methyl-phenyl)- C26H24NO4F 1.14 434.3 5-fluoro-3,4-dihydro-1H-isoquinoline-2- 433.17 LC-MS 1FA carboxylic acid benzyl ester 8 8-(5-Carboxymethyl-2-trifluoromethyl- C26H21NO4F4 1.15 488.3 phenyl)-5-fluoro-3,4-dihydro-1H- 487.14 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 9 8-(5-Carboxymethyl-2-chloro-phenyl)-5- C25H21NO4ClF 1.13 454.2 fluoro-3,4-dihydro-1H-isoquinoline-2- 453.11 LC-MS 1FA carboxylic acid benzyl ester 10 8-(5-Carboxymethyl-2-fluoro-phenyl)-5- C25H21NO4F2 1.09 438.2 fluoro-3,4-dihydro-1H-isoquinoline-2- 437.14 LC-MS 1FA carboxylic acid benzyl ester 11 8-(3-Carboxymethyl-4-chloro-phenyl)-5- C25H21NO4ClF 1.14 454.3 fluoro-3,4-dihydro-1H-isoquinoline-2- 453.11 LC-MS 1FA carboxylic acid benzyl ester 12 8-(3-Carboxymethyl-4-fluoro-phenyl)-5- C25H21NO4F2 1.10 438.2 fluoro-3,4-dihydro-1H-isoquinoline-2- 437.14 LC-MS 1FA carboxylic acid benzyl ester 13 8-(3-Carboxymethyl-4-methoxy- C26H24NO5F 1.10 450.3 phenyl)-5-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 14 8-(3-Carboxymethyl-5-fluoro-phenyl)-5- C25H21NO4F2 1.12 438.3 fluoro-3,4-dihydro-1H-isoquinoline-2- 437.14 LC-MS 1FA carboxylic acid benzyl ester 15 8-(3-Carboxymethyl-5-methoxy- C26H24NO5F 1.10 450.3 phenyl)-5-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 16 8-(3-Carboxymethyl-2-fluoro-phenyl)-5- C25H21NO4F2 1.09 438.3 fluoro-3,4-dihydro-1H-isoquinoline-2- 437.14 LC-MS 1FA carboxylic acid benzyl ester 17 6-(5-Carboxymethyl-2-methoxy- C27H26NO5F 1.08 464.3 phenyl)-9-fluoro-1,2,4,5-tetrahydro- 463.18 LC-MS 1FA benzo[d]azepine-3-carboxylic acid benzyl ester 18 4-(5-Carboxymethyl-2-methoxy- C25H22NO5F 1.06 436.2 phenyl)-7-fluoro-1,3-dihydro-isoindole- 435.15 LC-MS 1FA 2-carboxylic acid benzyl ester 19 8-(3-Carboxymethyl-5-chloro-phenyl)-5- C25H21NO4ClF 1.17 454.2 fluoro-3,4-dihydro-1H-isoquinoline-2- 453.11 LC-MS 1FA carboxylic acid benzyl ester 20 8-(5-Carboxymethyl-2-methanesulfonyl- C26H24NO6FS 0.94 498.3 phenyl)-5-fluoro-3,4-dihydro-1H- 497.13 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 21 8-(5-Carboxymethyl-2-trifluoromethoxy- C26H21NO5F4 1.17 504.3 phenyl)-5-fluoro-3,4-dihydro-1H- 503.14 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 22 8-(5-Carboxymethyl-2-isopropoxy- C28H28NO5F 1.16 478.3 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 23 8-(5-Carboxymethyl-2-fluoro-phenyl)- C25H22NO4F 1.06 420.2 3,4-dihydro-1H-isoquinoline-2- 419.15 LC-MS 1FA carboxylic acid benzyl ester 24 8-(3-Carboxymethyl-phenyl)-5-fluoro- C25H22NO4F 1.10 420.2 3,4-dihydro-1H-isoquinoline-2- 419.15 LC-MS 1FA carboxylic acid benzyl ester 25 8-(5-Carboxymethyl-2-methoxy- C27H27NO7S 0.90 510.3 phenyl)-5-methanesulfonyl-3,4-dihydro- 509.15 LC-MS 1FA 1H-isoquinoline-2-carboxylic acid benzyl ester 26 {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C28H23NO4F4 1.15 514.3 cyclopropanecarbonyl)-1,2,3,4- 513.16 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- trifluoromethoxy-phenyl}-acetic acid 27 {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C30H30NO4F 1.14 488.4 cyclopropanecarbonyl)-1,2,3,4- 487.22 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- isopropoxy-phenyl}-acetic acid 28 {4-Chloro-3-[5-fluoro-2-((1R,2R)-2- C27H23NO3ClF 1.11 464.2 phenyl-cyclopropanecarbonyl)-1,2,3,4- 463.14 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 29 {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C28H26NO5FS 0.91 508.3 cyclopropanecarbonyl)-1,2,3,4- 507.15 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methanesulfonyl-phenyl}-acetic acid 30 8-(2-Carboxymethyl-phenyl)-5-fluoro- C25H22NO4F 1.08 420.2 3,4-dihydro-1H-isoquinoline-2- 419.15 LC-MS 1FA carboxylic acid benzyl ester 31 8-(5-Carboxymethyl-2-methoxy- C26H23NO5F2 1.09 468.3 phenyl)-5,6-difluoro-3,4-dihydro-1H- 467.15 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 32 8-(5-Carboxymethyl-2-methoxy- C26H24NO5F 1.05 450.1 phenyl)-6-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 33 8-(5-Carboxymethyl-2-methoxy- C26H24NO5F 1.03 450.3 phenyl)-7-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 34 {3-[6-Fluoro-2-((1R,2R)-2-phenyl- C28H26NO4F 1.03 460.3 cyclopropanecarbonyl)-1,2,3,4- 459.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 35 {3-[7-Fluoro-2-((1R,2R)-2-phenyl- C28H26NO4F 1.00 460.3 cyclopropanecarbonyl)-1,2,3,4- 459.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 36 (±)-{3-[9-Fluoro-3-(trans-2-phenyl- C29H28NO4F 1.04 474.4 cyclopropanecarbonyl)-2,3,4,5- 473.20 LC-MS 1FA tetrahydro-1H-benzo[d]azepin-6-yl]-4- methoxy-phenyl}-acetic acid 37 (±)-{3-[7-Fluoro-2-(trans-2-phenyl- C27H24NO4F 1.02 446.3 cyclopropanecarbonyl)-2,3-dihydro-1H- 445.17 LC-MS 1FA isoindol-4-yl]-4-methoxy-phenyl}-acetic acid 38 {3-[5,7-Difluoro-2-((1R,2R)-2-phenyl- C28H25NO4F2 1.05 478.3 cyclopropanecarbonyl)-1,2,3,4- 477.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 39 8-(5-Carboxymethyl-2-methoxy- C26H23NO5F2 1.07 468.3 phenyl)-5,7-difluoro-3,4-dihydro-1H- 467.15 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 40 8-(4-Carboxymethyl-3-chloro-phenyl)-5- C25H21NO4ClF 1.16 454.1 fluoro-3,4-dihydro-1H-isoquinoline-2- 453.11 LC-MS 1FA carboxylic acid benzyl ester 41 8-(4-Carboxymethyl-phenyl)-5-fluoro- C25H22NO4F 1.10 420.3 3,4-dihydro-1H-isoquinoline-2- 419.15 LC-MS 1FA carboxylic acid benzyl ester

Amide Coupling and Subsequent Saponification

Method A: To a solution of 3-(4-fluorophenoxy)propionic acid (22 mg, 0.12 mmol, 1.2 eq.) in DCM/DMF 1:1 (1.00 mL), TBTU (39 mg, 0.12 mmol, 1.2 eq.) and Si-DEA (238 mg, 0.30 mmol, 3.0 eq.) were added in sequence. The mixture was stirred at r.t. for 30 min. A solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (38 mg, 0.10 mmol, 1.0 eq.) in DMF (0.25 mL) was added and the resulting mixture was stirred at r.t. for 1 hour. The mixture was filtered, the solid rinsed with DCM (3 mL), and the filtrate was concentrated in vacuo. To a solution of the residue in THF (1.0 mL), 1M aq. NaOH (1.0 mL) was added. The mixture was stirred at r.t. for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

Listed in Table 2 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 2 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 42 (3-{5-Fluoro-2-[3-(4-fluoro- C27H25NO5F2 1.01 482.3 phenoxy)-propionyl]-1,2,3,4- 481.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 43 {3-[5-Fluoro-2-(2-phenoxy-acetyl)- C26H24NO5F 0.97 450.3 1,2,3,4-tetrahydro-isoquinolin-8- 449.16 LC-MS 1FA yl]-4-methoxy-phenyl}-acetic acid 44 (3-{5-Fluoro-2-[2-(4-fluoro- C26H23NO5F2 0.98 468.3 phenoxy)-acetyl]-1,2,3,4- 467.15 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 45 (3-{5-Fluoro-2-[4-(2-fluoro-phenyl)- C28H27NO4F2 1.06 480.3 butyryl]-1,2,3,4-tetrahydro- 479.19 LC-MS 1FA isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 46 {3-[2-(2-Ethoxy-acetyl)-5-fluoro- C22H24NO5F 0.85 402.3 1,2,3,4-tetrahydro-isoquinolin-8- 401.16 LC-MS 1FA yl]-4-methoxy-phenyl}-acetic acid 47 {3-[2-(2-tert-Butoxy-acetyl)-5- C24H28NO5F 0.94 430.3 fluoro-1,2,3,4-tetrahydro- 429.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 48 (±)-(3-{5-Fluoro-2-[trans-2-(3- C28H25NO4F2 1.05 478.3 fluoro-phenyl)- 477.18 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 49 (3-{5-Fluoro-2-[2-(5-methoxy- C28H25N2O6F 0.96 505.3 benzo[d]isoxazol-3-yl)-acetyl]- 504.17 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl}-4-methoxy-phenyl)-acetic acid 50 {3-[5-Fluoro-2-(2,2,3,3- C26H30NO4F 1.05 440.4 tetramethyl- 439.22 LC-MS 1FA cyclopropanecarbonyl)-1,2,3,4- tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 51 {3-[5-Fluoro-2-(3-pyridin-3-yl- C26H25N2O4F 0.66 449.3 propionyl)-1,2,3,4-tetrahydro- 448.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 52 [3-(2-Cyclopropanecarbonyl-5- C22H22NO4F 0.88 384.2 fluoro-1,2,3,4-tetrahydro- 383.15 LC-MS 1FA isoquinolin-8-yl)-4-methoxy- phenyl]-acetic acid 53 {3-[2-(3-3,4-Dihydro-2H-quinolin- C30H31N2O4F 1.08 503.4 1-yl-propionyl)-5-fluoro-1,2,3,4- 502.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 54 {3-[5-Fluoro-2-(3-phenyl- C27H26NO4F 1.00 448.3 propionyl)-1,2,3,4-tetrahydro- 447.19 LC-MS 1FA isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 55 (±)-{3-[2-(2,2-Dimethyl- C24H26NO4F 0.95 412.3 cyclopropanecarbonyl)-5-fluoro- 411.19 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-4-methoxy-phenyl}-acetic acid 56 {3-[5-Fluoro-2-(3-o-tolyl- C28H28NO4F 1.04 462.3 propionyl)-1,2,3,4-tetrahydro- 461.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 57 (3-{5-Fluoro-2-[3-(3-methyl-indol- C30H29N2O4F 1.09 501.4 1-yl)-propionyl]-1,2,3,4-tetrahydro- 500.21 LC-MS 1FA isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 58 (3-{2-[2-(2-Chloro-benzyloxy)- C27H25NO5ClF 1.03 498.3 acetyl]-5-fluoro-1,2,3,4-tetrahydro- 497.14 LC-MS 1FA isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid 59 {3-[2-(3-2,3-Dihydro-indol-1-yl- C29H29N2O4F 1.02 489.4 propionyl)-5-fluoro-1,2,3,4- 488.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 60 (±)-{3-[5-Fluoro-2-(trans-2-phenyl- C28H26NO4F 1.04 460.3 cyclopropanecarbonyl)-1,2,3,4- 459.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 61 (3-{5-Fluoro-2-[3-(2-methyl-1H- C30H29N2O4F 0.98 501.4 indol-3-yl)-propionyl]-1,2,3,4- 500.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 62 (3-{5-Fluoro-2-[3-(1-methyl-1H- C30H29N2O4F 1.04 501.4 indol-3-yl)-propionyl]-1,2,3,4- 500.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 63 (3-{5-Fluoro-2-[3-(5-methoxy-1H- C30H29N2O5F 0.94 517.4 indol-3-yl)-propionyl]-1,2,3,4- 516.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid

Method B: A solution of (1R,2R)-2-(4-chloro-phenyl)-cyclopropanecarboxylic acid (20 mg, 0.10 mmol, 1.0 eq.) and [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (38 mg, 0.10 mmol, 1.0 eq.) in DMF (1.2 mL) was treated with 4-(dimethylamino)pyridine (37 mg, 0.30 mmol, 3.0 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol, 1.5 eq) and the resulting solution was stirred at r.t. for 18 hours. 1M aq. NaOH soln. (0.6 mL) was added. The solution was stirred at r.t. during 1 hour. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 3 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 3 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 64 (3-{2-[(1R,2R)-2-(4-Chloro-phenyl)- C28H25NO4ClF 1.10 494.3 cyclopropanecarbonyl]-5-fluoro- 493.15 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- 4-methoxy-phenyl)-acetic acid 65 (3-{5-Fluoro-2-[(1R,2R)-2-(3-fluoro- C28H25NO4F2 1.05 478.3 phenyl)-cyclopropanecarbonyl]- 477.18 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- 4-methoxy-phenyl)-acetic acid 66 (3-{5-Fluoro-2-[(1R,2R)-2-(2-fluoro- C28H25NO4F2 1.04 478.4 phenyl)-cyclopropanecarbonyl]- 477.18 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- 4-methoxy-phenyl)-acetic acid 67 {3-[5-Fluoro-2-(3-indazol-1-yl- C28H26N3O4F 0.95 488.3 propionyl)-1,2,3,4-tetrahydro- 487.19 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 68 (3-{5-Chloro-2-[(1R,2R)-2-(4-chloro- C28H25NO4Cl2 1.16 510.2 phenyl)-cyclopropanecarbonyl]- 509.12 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- 4-methoxy-phenyl)-acetic acid 69 (3-{5-Chloro-2-[(1R,2R)-2-(3-fluoro- C28H25NO4ClF 1.11 494.3 phenyl)-cyclopropanecarbonyl]- 493.15 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- 4-methoxy-phenyl)-acetic acid 70 (3-{5-Chloro-2-[(1R,2R)-2-(2-fluoro- C28H25NO4ClF 1.10 494.3 phenyl)-cyclopropanecarbonyl]- 493.15 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- 4-methoxy-phenyl)-acetic acid 71 {3-[5-Chloro-2-((1R,2R)-2-phenyl- C28H26NO4Cl 1.10 476.3 cyclopropanecarbonyl)-1,2,3,4- 475.16 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 72 {3-[5-Chloro-2-(3-indazol-1-yl- C28H26N3O4Cl 1.02 504.3 propionyl)-1,2,3,4-tetrahydro- 503.16 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 73 (3-{5-Chloro-2-[2-(2-chloro- C27H25NO5Cl2 1.09 514.3 benzyloxy)-acetyl]-1,2,3,4- 513.11 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 74 (3-{5-Chloro-2-[4-(2-fluoro-phenyl)- C28H27NO4ClF 1.12 496.3 butyryl]-1,2,3,4-tetrahydro- 495.16 LC-MS 1FA isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 75 (3-{5-Chloro-2-[3-(1-methyl-1H- C30H29N2O4Cl 1.10 517.4 indol-3-yl)-propionyl]-1,2,3,4- 516.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 76 {3-[5-Chloro-2-(3-phenyl-propionyl)- C27H26NO4Cl 1.07 464.3 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 463.16 LC-MS 1FA 4-methoxy-phenyl}-acetic acid 77 {3-[5-Chloro-2-(3-3,4-dihydro-2H- C30H31N2O4Cl 1.14 519.4 quinolin-1-yl-propionyl)-1,2,3,4- 518.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 78 {3-[5-Chloro-2-(3-2,3-dihydro-indol- C29H29N2O4Cl 1.09 505.0 1-yl-propionyl)-1,2,3,4-tetrahydro- 504.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 79 (3-{5-Chloro-2-[3-(2-methyl-1H- C30H29N2O4Cl 1.04 517.3 indol-3-yl)-propionyl]-1,2,3,4- 516.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 80 {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C28H26NO4F 1.04 460.3 cyclopropanecarbonyl)-1,2,3,4- 459.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 81 {3-[5-Fluoro-2-((1S,2S)-2-phenyl- C28H26NO4F 1.04 460.1 cyclopropanecarbonyl)-1,2,3,4- 459.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 82 [3-(2-Cyclopropanecarbonyl-5- C23H22NO4F3 0.98 434.2 trifluoromethyl-1,2,3,4-tetrahydro- 433.15 LC-MS 1FA isoquinolin-8-yl)-4-methoxy-phenyl]- acetic acid 83 (±)-{4-Methoxy-3-[2-(trans-2-phenyl- C29H26NO4F3 1.12 510.3 cyclopropanecarbonyl)-5- 509.18 LC-MS 1FA trifluoromethyl-1,2,3,4-tetrahydro- isoquinolin-8-yl]-phenyl}-acetic acid 84 {3-[5,6-Difluoro-2-((1R,2R)-2- C28H25NO4F2 1.07 478.3 phenyl-cyclopropanecarbonyl)- 477.18 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid 85 (3-{5-Fluoro-2-[(E)-(3-phenyl- C27H24NO4F 1.01 446.3 acryloyl)]-1,2,3,4-tetrahydro- 445.17 LC-MS 1FA isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 86 (3-{5-Fluoro-2-[(E)-3-(6-methoxy- C27H25N2O5F 0.95 477.3 pyridin-3-yl)-acryloyl]-1,2,3,4- 476.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 87 (3-{2-[(E)-3-(2,4-Dimethyl-thiazol-5- C26H25N2O4FS 0.92 481.3 yl)-acryloyl]-5-fluoro-1,2,3,4- 480.15 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 88 {3-[2-((E)-3-Benzothiazol-2-yl- C28H23N2O4FS 1.03 503.2 acryloyl)-5-fluoro-1,2,3,4-tetrahydro- 502.13 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 89 {3-[5-Fluoro-2-((E)-3-pyridin-3-yl- C26H23N2O4F 0.78 447.3 acryloyl)-1,2,3,4-tetrahydro- 446.16 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 90 (3-{2-[(E)-3-(2,5-Dimethyl-2H- C26H26N3O4F 0.89 464.3 pyrazol-3-yl)-acryloyl]-5-fluoro- 463.19 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- 4-methoxy-phenyl)-acetic acid 91 {3-[5-Fluoro-2-(3-pyridin-2-yl- C26H25N2O4F 0.66 449.3 propionyl)-1,2,3,4-tetrahydro- 448.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 92 (3-{5-Fluoro-2-[3-(6-methyl-pyridin- C27H27N2O4F 0.65 463.4 2-yl)-propionyl]-1,2,3,4-tetrahydro- 462.20 LC-MS 1FA isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 93 {3-[5-Fluoro-2-(3-pyrimidin-2-yl- C25H24N3O4F 0.80 450.3 propionyl)-1,2,3,4-tetrahydro- 449.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 94 (3-{5-Fluoro-2-[2-(pyridin-3-yloxy)- C25H23N2O5F 0.71 451.3 acetyl]-1,2,3,4-tetrahydro- 450.16 LC-MS 1FA isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 95 (±)-(3-{5-Fluoro-2-[trans-2-(2- C29H25NO4F4 1.08 528.3 trifluoromethyl-phenyl)- 527.17 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 96 (±)-(3-{5-Fluoro-2-[trans-2-(4- C29H28NO5F 1.02 490.4 methoxy-phenyl)- 489.20 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 97 (±)-(3-{2-[3-(4-Chloro-phenyl)-3- C33H29NO4ClF 1.16 558.3 phenyl-propionyl]-5-fluoro-1,2,3,4- 557.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 98 (±)-(3-{2-[trans-2-(2,4-Dichloro- C28H24NO4Cl2F 1.14 528.3 phenyl)-cyclopropanecarbonyl]-5- 527.11 LC-MS 1FA fluoro-1,2,3,4-tetrahydro- isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 99 {3-[8-Fluoro-2-((1R,2R)-2-phenyl- C28H26NO4F 1.04 460.3 cyclopropanecarbonyl)-1,2,3,4- 459.19 LC-MS 1FA tetrahydro-isoquinolin-5-yl]-4- methoxy-phenyl}-acetic acid 100 {3-[8-Fluoro-2-(4-phenyl-butyryl)- C28H28NO4F 1.06 462.3 1,2,3,4-tetrahydro-isoquinolin-5-yl]- 461.20 LC-MS 1FA 4-methoxy-phenyl}-acetic acid 101 {3-[8-Fluoro-2-(3-phenyl-propionyl)- C27H26NO4F 1.01 448.3 1,2,3,4-tetrahydro-isoquinolin-5-yl]- 447.19 LC-MS 1FA 4-methoxy-phenyl}-acetic acid 102 {3-[8-Fluoro-2-(3-phenoxy- C27H26NO5F 1.00 464.3 propionyl)-1,2,3,4-tetrahydro- 463.18 LC-MS 1FA isoquinolin-5-yl]-4-methoxy-phenyl}- acetic acid 103 (3-{2-[2-(2-Chloro-benzyloxy)- C27H25NO5ClF 1.03 498.3 acetyl]-8-fluoro-1,2,3,4-tetrahydro- 497.14 LC-MS 1FA isoquinolin-5-yl}-4-methoxy-phenyl)- acetic acid 104 {3-[2-(3-3,4-Dihydro-2H-quinolin-1- C30H31N2O4F 1.08 503.4 yl-propionyl)-8-fluoro-1,2,3,4- 502.23 LC-MS 1FA tetrahydro-isoquinolin-5-yl]-4- methoxy-phenyl}-acetic acid 105 (3-{8-Fluoro-2-[3-(1-methyl-1H- C30H29N2O4F 1.04 501.4 indol-3-yl)-propionyl]-1,2,3,4- 500.21 LC-MS 1FA tetrahydro-isoquinolin-5-yl}-4- methoxy-phenyl)-acetic acid

Method C: To a solution of (R)-3-phenylbutyric acid (19 mg, 0.12 mmol, 1 eq.) in DCM (2 mL), DIPEA (0.1 mL, 0.58 mmol, 5 eq.) and TBTU (37 mg, 0.12 mmol, 1 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 minutes. Then [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (40 mg, 0.12 mmol, 1 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in DMF (0.8 mL). 1M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 3 hours. The solution was carefully neutralized with formic acid (0.5 mL), purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 4 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 4 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 106 {3-[5-Fluoro-2-((R)-3-phenyl- C28H28NO4F 1.04 462.3 butyryl)-1,2,3,4-tetrahydro- 461.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 107 {3-[5-Fluoro-2-((S)-3-phenyl- C28H28NO4F 1.04 462.3 butyryl)-1,2,3,4-tetrahydro- 461.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 108 {3-[5-Fluoro-2-(3-methyl-3-phenyl- C29H30NO4F 1.08 476.3 butyryl)-1,2,3,4-tetrahydro- 475.22 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 109 (±)-{3-[5-Fluoro-2-(2-methyl-3- C28H28NO4F 1.05 462.3 phenyl-propionyl)-1,2,3,4- 461.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 110 {3-[5-Fluoro-2-(indane-2-carbonyl)- C28H26NO4F 1.06 460.3 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 459.19 LC-MS 1FA 4-methoxy-phenyl}-acetic acid 111 {3-[5-Fluoro-2-(2-indan-2-yl-acetyl)- C29H28NO4F 1.08 474.4 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 473.20 LC-MS 1FA 4-methoxy-phenyl}-acetic acid 112 (±)-{3-[5-Fluoro-2-(indane-1- C28H26NO4F 1.03 460.3 carbonyl)-1,2,3,4-tetrahydro- 459.19 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 113 (±)-{3-[2-(Chroman-3-carbonyl)-5- C28H26NO5F 1.04 476.3 fluoro-1,2,3,4-tetrahydro- 475.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 114 (±)-{3-[5-Fluoro-2-(4-oxo-1,2,3,4- C29H26NO5F 0.96 488.3 tetrahydro-naphthalene-2-carbonyl)- 487.18 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid 115 (±)-{3-[2-(Chroman-2-carbonyl)-5- C28H26NO5F 1.04 476.3 fluoro-1,2,3,4-tetrahydro- 475.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 116 (±)-{3-[2-(Bicyclo[4.2.0]octa- C27H24NO4F 1.01 446.3 1(6),2,4-triene-7-carbonyl)-5-fluoro- 445.17 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid 117 {3-[5-Fluoro-2-(4-phenyl-butyryl)- C28H28NO4F 1.07 462.3 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 461.20 LC-MS 1FA 4-methoxy-phenyl}-acetic acid 118 {3-[5-Fluoro-2-(4-oxo-4-phenyl- C28H26NO5F 0.99 476.3 butyryl)-1,2,3,4-tetrahydro- 475.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 119 (3-{5-Fluoro-2-[2-(1-methyl-1H- C29H27N2O4F 1.01 487.3 indol-3-yl)-acetyl]-1,2,3,4- 486.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 120 (±)-2-{3-[5-Fluoro-2-((1R,2R)-2- C29H28NO4F 1.10 474.3 phenyl-cyclopropanecarbonyl)- 473.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-propionic acid

Method D: To a solution of 2-(1,2-benzisoxazol-3-yl)acetic acid (24 mg, 0.13 mmol, 1 eq.) in DCM (1 mL), 1-hydroxybenzotriazole hydrate (18 mg, 0.13 mmol, 1 eq.) and N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol, 1 eq.) were added in sequence. The resulting solution was stirred at r.t. for 2 min. Then a solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (46 mg, 0.13 mmol, 1 eq.) and NEt₃ (37 μL, 0.27 mmol, 2 eq.) in DCM (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in DMF (0.8 mL). 1M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 3 hours. The solution was carefully neutralized with formic acid (0.5 mL), purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 5 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 5 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 121 {3-[2-(2-Benzo[d]isoxazol-3-yl- C27H23N2O5F 0.97 475.3 acetyl)-5-fluoro-1,2,3,4-tetrahydro- 474.16 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 122 (±)-{3-[5-Fluoro-2-(3-oxo-indane-1- C28H24NO5F 0.91 474.3 carbonyl)-1,2,3,4-tetrahydro- 473.16 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 123 (±)-{3-[5-Fluoro-2-(1,2,3,4- C29H28NO4F 1.08 474.3 tetrahydro-naphthalene-2-carbonyl)- 473.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid 124 {3-[5-Fluoro-2-(2-1H-indazol-3-yl- C27H24N3O4F 0.88 474.3 acetyl)-1,2,3,4-tetrahydro- 473.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 125 (3-{5-Fluoro-2-[3-(3-methyl-indazol- C29H28N3O4F 1.01 502.3 1-yl)-propionyl]-1,2,3,4-tetrahydro- 501.21 LC-MS 1FA isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 126 (3-{5-Fluoro-2-[3-(5-fluoro-indazol- C28H25N3O4F2 0.98 506.3 1-yl)-propionyl]-1,2,3,4-tetrahydro- 505.18 LC-MS 1FA isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 127 {3-[2-(2-Cyclohexyl-acetyl)-5-fluoro- C26H30NO4F 1.08 440.3 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 439.22 LC-MS 1FA 4-methoxy-phenyl}-acetic acid 128 (3-{5-Fluoro-2-[2-(1-hydroxy- C26H30NO5F 0.98 456.3 cyclohexyl)-acetyl]-1,2,3,4- 455.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 129 {3-[2-(3,3-Dimethyl-butyryl)-5-fluoro- C24H28NO4F 1.01 414.3 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 413.20 LC-MS 1FA 4-methoxy-phenyl}-acetic acid

Urea Formation and Subsequent Saponification

To a solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (57 mg, 0.15 mmol, 1.00 eq) and triethylamine (63 μl, 0.45 mmol, 3.00 eq) in MeCN (1.0 mL), a solution of 2-fluorobenzyl isocyanate (25 mg, 0.16 mmol, 1.05 eq.) in MeCN (1.0 mL) was added. The mixture was stirred at r.t. for 18 hours. 1M aq. NaOH (0.8 mL) was added. The mixture was stirred at r.t. for 18 hours. Formic acid (0.2 mL) was added. The mixture was then purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 6 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding isocyanate as starting materials.

TABLE 6 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 130 {3-[5-Fluoro-2-(2-fluoro- C26H24N2O4F2 0.95 467.3 benzylcarbamoyl)-1,2,3,4- 466.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 131 {3-[5-Fluoro-2-(3-fluoro- C26H24N2O4F2 0.95 467.3 benzylcarbamoyl)-1,2,3,4- 466.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 132 {3-[5-Fluoro-2-(4-fluoro- C26H24N2O4F2 0.95 467.3 benzylcarbamoyl)-1,2,3,4- 466.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 133 [3-(5-Fluoro-2- C27H27N2O4F 0.97 463.3 phenethylcarbamoyl-1,2,3,4- 462.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl)-4- methoxy-phenyl]-acetic acid 134 {3-[2-(2-Chloro-benzylcarbamoyl)- C26H24N2O4ClF 0.98 483.0 5-fluoro-1,2,3,4-tetrahydro- 482.14 LC-MS 1FA isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 135 {3-[5-Fluoro-2-(2-methoxy- C27H27N2O5F 0.95 479.3 benzylcarbamoyl)-1,2,3,4- 478.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 136 [3-(2-Benzylcarbamoyl-5-fluoro- C26H25N2O4F 0.94 449.3 1,2,3,4-tetrahydro-isoquinolin-8- 448.18 LC-MS 1FA yl)-4-methoxy-phenyl]-acetic acid 137 [3-(5-Fluoro-2-propylcarbamoyl- C22H25N2O4F 0.87 401.3 1,2,3,4-tetrahydro-isoquinolin-8- 400.18 LC-MS 1FA yl)-4-methoxy-phenyl]-acetic acid

Carbamate Formation and Subsequent Saponification

Method A: To a solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (38 mg, 0.10 mmol, 1.0 eq.) and DIPEA (42 μL, 0.25 mmol, 2.5 eq.) in DCM (1.5 mL), carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 3-fluoro-benzyl ester (32 mg, 0.12 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 1 hour. The reaction was quenched with 1M aq. citric acid soln. (1.5 mL). The layers were separated over phase separators. The aq. phase was extracted with DCM (3×). The comb. org. phases were concentrated in vacuo. To a solution of the residue in DMF (0.4 mL), 1M aq. NaOH (0.5 mL) was added. The solution was stirred at r.t. for 18 hours. Formic acid (0.2 mL) was added. The resulting solution was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 7 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding carbonate 3 as starting materials.

TABLE 7 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 138 8-(5-Carboxymethyl-2-methoxy- C26H23NO5F2 1.07 468.3 phenyl)-5-fluoro-3,4-dihydro-1H- 467.15 LC-MS 1FA isoquinoline-2-carboxylic acid 3- fluoro-benzyl ester 139 8-(5-Carboxymethyl-2-methoxy- C26H23NO5F2 1.07 468.3 phenyl)-5-fluoro-3,4-dihydro-1H- 467.15 LC-MS 1FA isoquinoline-2-carboxylic acid 4- fluoro-benzyl ester 140 (±)-8-[5-(1-Carboxy-ethyl)-2- C27H25NO5F2 1.13 482.2 methoxy-phenyl]-5-fluoro-3,4- 481.17 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-fluoro-benzyl ester

Method B: To a solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (38 mg, 0.10 mmol, 1.0 eq) and DIPEA (42 μL, 0.25 mmol, 2.5 eq) in DCM (1.5 mL), ethyl chloroformate (12 μL, 0.12 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 1 hour. The reaction was quenched with 1M aq. citric acid soln. (1.5 mL). The layers were separated over phase separators. The aq. phase was extracted with DCM (3×). The comb. org. phases were concentrated in vacuo. To a solution of the residue in DMF (0.4 mL), 1M aq. NaOH (0.5 mL) was added. The solution was stirred at r.t. for 18 hours. Formic acid (0.2 mL) was added. The resulting solution was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 8 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding chloroformate as starting materials.

TABLE 8 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 141 8-(5-Carboxymethyl-2-methoxy- C21H22NO5F 0.95 388.2 phenyl)-5-fluoro-3,4-dihydro-1H- 387.15 LC-MS 1FA isoquinoline-2-carboxylic acid ethyl ester 142 8-(5-Carboxymethyl-2-methoxy- C23H26NO5F 1.06 416.3 phenyl)-5-fluoro-3,4-dihydro-1H- 415.18 LC-MS 1FA isoquinoline-2-carboxylic acid isobutyl ester 143 8-(5-Carboxymethyl-2-methoxy- C22H24NO5F 1.01 402.2 phenyl)-5-fluoro-3,4-dihydro-1H- 401.16 LC-MS 1FA isoquinoline-2-carboxylic acid isopropyl ester 144 8-(3-Carboxymethoxy-5-chloro- C25H21NO5ClF 1.16 470.2 phenyl)-5-fluoro-3,4-dihydro-1H- 469.11 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 145 8-(2-Carboxymethoxy-5-chloro- C25H21NO5ClF 1.16 470.2 phenyl)-5-fluoro-3,4-dihydro-1H- 469.11 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester

Carbamate Formation and Concomitant Saponification

To a solution of 8-(5-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-nitro-phenyl ester (56 mg, 0.1 mmol, 1 eq.) and 2-fluorobenzyl alcohol (38 mg, 0.3 mmol, 3 eq.) in THF (1.7 mL), potassium tert-butoxide (33.7 mg, 0.3 mmol, 3 eq.) was added. The mixture was stirred at r.t. for 2 hours. The solvent was removed in vacuo. The residue was dissolved in MeCN/H₂O 1:1 (1.0 mL), formic acid (0.2 mL) was added followed by DMF (0.5 mL). The resulting solution was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as pale yellow foam.

Listed in Table 9 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding nitrophenyl carbamate 5 and the corresponding alcohol as starting materials.

TABLE 9 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 146 8-(5-Carboxymethyl-2-methoxy- C26H23NO5F2 1.07 468.3 phenyl)-5-fluoro-3,4-dihydro-1H- 467.15 LC-MS 1FA isoquinoline-2-carboxylic acid 2- fluoro-benzyl ester 147 8-(5-Carboxymethyl-2-methoxy- C26H22NO5F3 1.08 486.3 phenyl)-5-fluoro-3,4-dihydro-1H- 485.15 LC-MS 1FA isoquinoline-2-carboxylic acid 2,3- difluoro-benzyl ester 148 8-(5-Carboxymethyl-2-methoxy- C24H24N3O5F 0.89 454.3 phenyl)-5-fluoro-3,4-dihydro-1H- 453.17 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-2H-pyrazol-3-ylmethyl ester 149 8-(5-Carboxymethyl-2-methoxy- C25H26N3O5F 0.91 468.4 phenyl)-5-fluoro-3,4-dihydro-1H- 467.19 LC-MS 1FA isoquinoline-2-carboxylic acid 2,5- dimethyl-2H-pyrazol-3-ylmethyl ester 150 8-(5-Carboxymethyl-2-methoxy- C24H23N2O5FS 0.95 471.3 phenyl)-5-fluoro-3,4-dihydro-1H- 470.13 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-thiazol-4-ylmethyl ester 151 8-(5-Carboxymethyl-2-methoxy- C24H23N2O5FS 0.93 471.3 phenyl)-5-fluoro-3,4-dihydro-1H- 470.13 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-thiazol-5-ylmethyl ester 152 8-(5-Carboxymethyl-2-methoxy- C24H22N3O5F 0.84 452.3 phenyl)-5-fluoro-3,4-dihydro-1H- 451.15 LC-MS 1FA isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester 153 8-(5-Carboxymethyl-2-methoxy- C25H25N2O5FS 0.92 485.3 phenyl)-5-fluoro-3,4-dihydro-1H- 484.15 LC-MS 1FA isoquinoline-2-carboxylic acid 2-(4- methyl-thiazol-5-yl)-ethyl ester

Suzuki Cross-Coupling and Subsequent Saponification

Method A: To a mixture under N₂ of 8-bromo-5-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (214 mg, 0.50 mmol, 1.00 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (203 mg, 0.50 mmol, 1.00 eq.) and sodium carbonate (212 mg, 2.00 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (10.0 mL), tetrakis(triphenylphosphine) palladium (0) (29 mg, 0.03 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (20 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄, and filtered through Celite. The filtrate was concentrated in vacuo. To a solution of the residue in DMF (2.2 mL), 1M aq. NaOH soln. (0.6 mL) was added. The solution was stirred at r.t. for 18 hours. Formic acid was added (0.2 mL). The resulting solution was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 10 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 7 as starting material.

TABLE 10 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 154 8-(5-Carboxymethyl-2-methoxy- C26H24NO5Cl 1.13 466.3 phenyl)-5-chloro-3,4-dihydro-1H- 465.13 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 155 8-(5-Carboxymethyl-2-methoxy- C27H27NO5 1.08 446.3 phenyl)-5-methyl-3,4-dihydro-1H- 445.19 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 156 8-(5-Carboxymethyl-2-methoxy- C27H27NO6 1.05 462.3 phenyl)-5-methoxy-3,4-dihydro- 461.18 LC-MS 1FA 1H-isoquinoline-2-carboxylic acid benzyl ester 157 8-(5-Carboxymethyl-2-methoxy- C26H24NO5F 1.06 450.2 phenyl)-5-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 158 8-(5-Carboxymethyl-2-methoxy- C27H24NO5F3 1.15 500.3 phenyl)-5-trifluoromethyl-3,4- 499.16 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 159 5-(5-Carboxymethyl-2-methoxy- C26H24NO5F 1.07 450.1 phenyl)-8-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester

Method B: To a mixture under N₂ of [5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-((1R,2R)-2-phenyl-cyclopropyl)-methanone (53 mg, 0.125 mmol, 1.00 eq.), (3-bromo-4-trifluoromethoxy-phenoxy)-acetic acid ethyl ester (43 mg, 0.125 mmol, 1.00 eq.) and sodium carbonate (66 mg, 0.63 mmol, 5.00 eq.) in toluene/EtOH/water 20:4:1 (1.9 mL), tetrakis(triphenylphosphine) palladium (0) (7.2 mg, 0.006 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue was redissolved in DMF (0.6 mL) and 1M aq. NaOH (0.25 mL) was added. The resulting mixture was stirred at r.t. for 30 min. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 11 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding halogenated compound 9 as starting material.

TABLE 11 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 160 {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C28H23NO5F4 1.14 530.3 cyclopropanecarbonyl)-1,2,3,4- 529.15 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- trifluoromethoxy-phenoxy}-acetic acid 161 {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C30H30NO5F 1.13 504.4 cyclopropanecarbonyl)-1,2,3,4- 503.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- isopropoxy-phenoxy}-acetic acid

Method C: To a mixture under N₂ of 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (52 mg, 0.125 mmol, 1.00 eq.), (3-bromo-4-trifluoromethoxy-phenoxy)-acetic acid ethyl ester (43 mg, 0.125 mmol, 1.00 eq.) and sodium carbonate (66 mg, 0.63 mmol, 5.00 eq.) in toluene/EtOH/water 20:4:1 (1.9 mL), tetrakis(triphenylphosphine) palladium (0) (7.2 mg, 0.006 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered over celite, and concentrated in vacuo. The residue was redissolved in DMF (0.6 mL) and 1M aq. NaOH (0.25 mL) was added. The resulting mixture was stirred at r.t. for 30 min. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 12 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding halogenated compound 9 as starting material.

TABLE 12 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 162 8-(5-Carboxymethoxy-2- C26H21NO6F4 1.16 520.3 trifluoromethoxy-phenyl)-5-fluoro- 519.13 LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 163 8-(5-Carboxymethoxy-2- C28H28NO6F 1.15 494.3 isopropoxy-phenyl)-5-fluoro-3,4- 493.19 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 164 8-(4-Carboxymethyl-2-fluoro- C25H21NO4F2 1.11 438.2 phenyl)-5-fluoro-3,4-dihydro-1H- 437.14 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 165 8-(4-Carboxymethyl-2-chloro- C25H21NO4ClF 1.14 454.3 phenyl)-5-fluoro-3,4-dihydro-1H- 453.11 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 166 8-(4-Carboxymethyl-2-methoxy- C26H24NO5F 1.10 450.2 phenyl)-5-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester

Method D: A mixture under N₂ of palladium(II)acetate (0.2 mg, 0.001 mmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.8 mg, 0.002 mmol, 0.02 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (86.4 mg, 0.150 mmol, 1.50 eq.) and potassium phosphate (42.5 mg, 0.200 mmol, 2.00 eq.) in toluene (0.3 mL) and water (20 was stirred at r.t. for 2 min. A solution of (7-chloro-benzo[1,3]dioxol-5-yl)-acetic acid ethyl ester (24.3 mg, 0.100 mmol, 1.00 eq.) in toluene (0.3 mL) was added and the mixture was stirred at 100° C. for 66 hours. The mixture was allowed to cool to r.t., filtered through celite and concentrated in vacuo. The residue was dissolved in DMF (0.5 mL) and 2M aq. NaOH (0.2 mL) was added. The resulting mixture was stirred at r.t. for 18 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo.

Listed in Table 13 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding halogenated compound 9 as starting material.

TABLE 13 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 167 8-(6-Carboxymethyl- C26H22NO6F 1.07 464.3 benzo[1,3]dioxol-4-yl)-5-fluoro-3,4- 463.14 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 168 8-(7-Carboxymethyl-2,3-dihydro- C27H24NO6F 1.05 478.3 benzo[1,4]dioxin-5-yl)-5-fluoro-3,4- 477.16 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester

Example 169 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H24N2O5, MW=456.17)

To an ice-cooled suspension of 5-cyano-8-hydroxy-3,4-dihydro-1H-isoquinoline-2-5 carboxylic acid benzyl ester (73 mg, 0.24 mmol, 1.0 eq.) in DCM (4.4 mL), triethylamine (99 μL, 0.71 mmol, 3.0 eq.) and trifluoromethanesulfonic anhydride (61 μL, 0.355 mmol, 1.5 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (10 mL) and washed with sat. aq. NaHCO₃ soln. (2×). The org. layer was dried over MgSO₄, filtered, and concentrated in vacuo. To a mixture under N₂ of the triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (97 mg, 0.24 mmol, 1.0 eq.), and sodium carbonate (100 mg, 0.95 mmol, 4.0 eq.) in toluene/EtOH/water 20:4:1 (4.8 mL), tetrakis(triphenylphosphine) palladium (0) (14 mg, 12 μmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×5 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 27 fractions of 30 mL, Heptane+10% AcOEt to Heptane+40% AcOEt). To a solution of the residue in DMF (1 mL), 1M aq. NaOH soln. (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. Formic acid was added (0.2 mL). The mixture was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a white foam.

LC-MS 1FA: t_(R)=1.00 min; [M+H]⁺=457.3

Example 170 8-(5-Carboxymethyl-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H25NO5, MW=431.17)

To an ice-cooled solution of 8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (113 mg, 0.40 mmol, 1.00 eq.) in DCM (1 mL), NEt₃ (0.17 mL, 1.20 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (0.10 mL, 0.60 mmol, 1.50 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (50 mL) and washed with sat. aq. NaHCO₃ soln. (2×25 mL). The org. layer was dried over MgSO₄ and concentrated in vacuo. To a mixture under N₂ of the triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (128 mg, 0.40 mmol, 1.00 eq.), and sodium carbonate (170 mg, 1.60 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (2.5 mL), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 17 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄, and concentrated in vacuo. The residue was partially purified by CC (SiO₂, Hept/AcOEt 8:2 to 7:3) to give an yellow oil. The residue was dissolved in THF (3 mL) and 1M aq. NaOH (0.6 mL) was added. The resulting solution was stirred at r.t. for 68 hours. The org. solvent was removed in vacuo. The residue was diluted with water (10 mL) and acidified with 1M aq. HCl. The mixture was extracted with DCM/THF 3:1 (3×5 mL). The comb. org. phases were concentrated in vacuo. The crude product was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.

LC-MS 1FA: t_(R)=1.03 min; [M+H]⁺=432.3

Example 171 (±)-8-[5-(1-Carboxy-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H26NO5F, MW=463.18)

To a mixture under N₂ of 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (82 mg, 0.20 mmol, 1.00 eq.), (±)-2-(3-bromo-4-methoxy-phenyl)-propionic acid ethyl ester (63 mg, 0.20 mmol, 1.00 eq.) and sodium carbonate (85 mg, 0.80 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (4 mL), tetrakis(triphenylphosphine) palladium (0) (12 mg, 0.01 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×5 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. To a solution of the previous residue in DMF (0.9 mL), 1M aq. NaOH soln. (1.3 mL) was added. The mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was redissolved in THF (2 mL) and water (2 mL). Lithiumhydroxide monohydrate (23 mg, 0.54 mmol, 2.71 eq.) was added and the mixture was stirred at 50° C. for 18 hours. Formic acid was added (0.2 mL). The solution was diluted with DCM. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. layers were dried over MgSO₄, filtered and concentrated in vacuo.

The residue was purified by prep. HPLC (column: Waters Xbridge, 19×30 mm, 5 um, UV/MS, acidic conditions) and concentrated in vacuo to give the acid as a pale yellow solid. LC-MS 1FA: t_(R)=1.11 min; [M+H]⁺=464.3

Example 172 8-(4-Carboxymethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H22NO5F, MW=435.15)

To a mixture under N₂ of 8-bromo-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (72.8 mg, 0.2 mmol, 1.0 eq.), 4-hydroxybenzeneboronic acid (41.4 mg, 0.3 mmol, 1.5 eq.) and sodium carbonate (127.2 mg, 1.2 mmol, 6.0 eq.) in toluene/MeOH/water 20:4:1 (4 mL), tetrakis(triphenylphosphine) palladium (0) (17.4 mg, 0.015 mmol, 0.08 eq) was added and the mixture was stirred under reflux at 100° C. for 72 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×5 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+40% AcOEt) to yield a colorless oil. To a solution of the colorless oil and K₂CO₃ (82.9 mg, 0.6 mmol, 3.0 eq.) in DMF (0.7 mL), ethyl bromoacetate (66 pt, 0.6 mmol, 3.0 eq.) was added. The mixture was stirred at r.t. for 2 hours. 1M aq. NaOH soln. (0.54 mL) was added and the mixture stirred at r.t. for 18 hours. Formic acid was added (0.2 mL). The resulting acidic mixture was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a yellow oil.

LC-MS 1FA: t_(R)=1.10 min; [M+H]⁺=436.2

Alkylation and Subsequent Saponification

Method A: To a solution of 8-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (50 mg, 0.13 mmol, 1.0 eq.) and potassium carbonate anhydrous (55 mg, 0.40 mmol, 3.0 eq.) in DMF (1.5 mL), ethyl bromoacetate (22 μL, 0.20 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with water (10 mL) and AcOEt (20 mL). The layers were separated. The aq. phase was extracted with AcOEt (2×10 mL). The comb. org. phases were washed with water (1×10 mL), sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄, and concentrated in vacuo. To a solution of the residue in THF (1 mL), 1M aq. NaOH (0.2 mL) was added. The resulting solution was stirred at r.t. for 4 hours. The org. solvent was removed in vacuo. The residue was diluted with water (2 mL) and acidified with 1M aq. HCl.

The mixture was extracted with DCM/THF 2:1 (3×6 mL). The comb. org. phases were concentrated in vacuo. The crude product was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 14 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding phenols 13 as starting material.

TABLE 14 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 173 8-(2-Carboxymethoxy-5-fluoro- C25H22NO5F 1.08 436.2 phenyl)-3,4-dihydro-1H- 435.15 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 174 8-[2-(3-Carboxy-propoxy)-5-fluoro- C27H26NO5F 1.13 464.3 phenyl]-3,4-dihydro-1H- 463.18 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester

Method B: To a solution of 5-fluoro-8-(3-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (84 mg, 0.22 mmol, 1.0 eq.) and potassium carbonate (91 mg, 0.66 mmol, 3.0 eq.) in DMF (0.7 mL), ethyl bromoacetate (36 μL, 0.33 mmol, 3.0 eq.) was added. The mixture was stirred at r.t. for 2 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. phases were washed with water, sat. aq. NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo. To a solution of the residue in DMF (1.0 mL), 1M aq. NaOH soln. (0.3 mL) was added. The solution was stirred at r.t. for 18 hours. Formic acid was added (0.2 mL). The resulting solution was purified by prep. HPLC (column: Waters Xbridge, 19×30 mm, 5 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 15 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding phenol 13 as starting material.

TABLE 15 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 175 8-(3-Carboxymethoxy-phenyl)-5- C25H22NO5F 1.09 436.2 fluoro-3,4-dihydro-1H- 435.15 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 176 8-(5-Carboxymethoxy-2-chloro- C25H21NO5ClF 1.13 470.2 phenyl)-5-fluoro-3,4-dihydro-1H- 469.11 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 177 8-(5-Carboxymethoxy-2-methoxy- C26H24NO6F 1.05 466.2 phenyl)-5-fluoro-3,4-dihydro-1H- 465.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 178 8-(5-Carboxymethoxy-2-chloro- C25H21NO5Cl2 1.19 486.0 phenyl)-5-chloro-3,4-dihydro-1H- 485.08 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 179 8-(5-Carboxymethoxy-2-chloro- C26H24NO5Cl 1.14 466.1 phenyl)-5-methyl-3,4-dihydro-1H- 465.13 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 180 8-(5-Carboxymethoxy-2-chloro- C26H21NO5ClF3 1.20 520.2 phenyl)-5-trifluoromethyl-3,4- 519.11 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 181 8-(5-Carboxymethoxy-2-chloro- C25H22NO5Cl 1.09 452.2 phenyl)-3,4-dihydro-1H- 451.12 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 182 {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C28H26NO5F 1.02 476.3 cyclopropanecarbonyl)-1,2,3,4- 475.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenoxy}-acetic acid

Amide Coupling and Subsequent Saponification

To a solution of 3-(1-methyl-1H-indol-3-yl)-propionic acid (26 mg, 0.13 mmol, 1.1 eq.) in DCM (2 mL), DIPEA (80 μL, 0.47 mmol, 4.0 eq.) and TBTU (41 mg, 0.13 mmol, 1.1 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. Then ethyl 2-(4-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methoxyphenyl)acetate (40 mg, 0.12 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in DMF (0.8 mL). 1M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 3 hours. The solution was carefully neutralized with formic acid (0.5 mL), and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 16 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding acid as starting material.

TABLE 16 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 183 (4-{5-Fluoro-2-[3-(1-methyl-1H- C30H29N2O4F 1.06 501.3 indol-3-yl)-propionyl]-1,2,3,4- 500.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-3- methoxy-phenyl)-acetic acid 184 {4-[5-Fluoro-2-((1R,2R)-2-phenyl- C28H26NO4F 1.06 460.2 cyclopropanecarbonyl)-1,2,3,4- 459.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-3- methoxy-phenyl}-acetic acid 185 (4-{5-Fluoro-2-[4-(2-fluoro-phenyl)- C28H27NO4F2 1.08 480.2 butyryl]-1,2,3,4-tetrahydro- 479.19 LC-MS 1FA isoquinolin-8-yl}-3-methoxy- phenyl)-acetic acid 186 (4-{5-Fluoro-2-[3-(2-methyl-1H- C30H29N2O4F 1.00 501.3 indol-3-yl)-propionyl]-1,2,3,4- 500.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-3- methoxy-phenyl)-acetic acid 187 {4-[5-Fluoro-2-(4-phenyl-butyryl)- C28H28NO4F 1.07 462.3 1,2,3,4-tetrahydro-isoquinolin-8- 461.20 LC-MS 1FA yl]-3-methoxy-phenyl}-acetic acid 188 {4-[5-Fluoro-2-(3-methyl-3-phenyl- C29H30NO4F 1.09 476.3 butyryl)-1,2,3,4-tetrahydro- 475.22 LC-MS 1FA isoquinolin-8-yl]-3-methoxy- phenyl}-acetic acid 189 {4-[5-Fluoro-2-((R)-3-phenyl- C28H28NO4F 1.05 462.3 butyryl)-1,2,3,4-tetrahydro- 461.20 LC-MS 1FA isoquinolin-8-yl]-3-methoxy- phenyl}-acetic acid 190 (4-{5-Fluoro-2-[3-(5-fluoro-indazol- C28H25N3O4F2 0.99 506.2 1-yl)-propionyl]-1,2,3,4-tetrahydro- 505.18 LC-MS 1FA isoquinolin-8-yl}-3-methoxy- phenyl)-acetic acid 191 {4-[2-(3-2,3-Dihydro-indol-1-yl- C29H29N2O4F 1.04 489.3 propionyl)-5-fluoro-1,2,3,4- 488.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-3- methoxy-phenyl}-acetic acid 192 (4-{5-Fluoro-2-[3-(4-fluoro- C27H25NO5F2 1.03 482.2 phenoxy)-propionyl]-1,2,3,4- 481.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-3- methoxy-phenyl)-acetic acid 193 (4-{2-[2-(2-Chloro-benzyloxy)- C27H25NO5ClF 1.05 498.2 acetyl]-5-fluoro-1,2,3,4-tetrahydro- 497.14 LC-MS 1FA isoquinolin-8-yl}-3-methoxy- phenyl)-acetic acid 194 {4-[5-Fluoro-2-(3-o-tolyl- C28H28NO4F 1.06 462.3 propionyl)-1,2,3,4-tetrahydro- 461.20 LC-MS 1FA isoquinolin-8-yl]-3-methoxy- phenyl}-acetic acid

Suzuki Cross-Coupling and Subsequent Saponification

To a mixture under N₂ of 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (97 mg, 0.20 mmol, 1.00 eq.), (3-bromo-4-ethoxy-phenyl)-acetic acid ethyl ester (57 mg, 0.20 mmol, 1.00 eq.) and sodium carbonate (106 mg, 1.00 mmol, 5.00 eq.) in toluene/EtOH/Water 20:4:1 (3 mL), tetrakis(triphenylphosphine) palladium (0) (11.6 mg, 0.01 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered over celite, and concentrated in vacuo. The residue, redissolved in MeCN/H₂O 1:1 (2 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo. The residue was redissolved in DMF (1 mL) and 2M aq. NaOH (0.4 ml) was added. The resulting mixture was stirred at r.t. for 18 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to yield the desired acid.

Listed in Table 17 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound 9 as starting material.

TABLE 17 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 195 8-(5-Carboxymethyl-2-ethoxy- C27H26NO5F 1.12 464.3 phenyl)-5-fluoro-3,4-dihydro-1H- 463.18 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 196 8-(5-Carboxymethyl-2- C29H28NO5F 1.16 490.2 cyclopropylmethoxy-phenyl)-5- 489.20 LC-MS 1FA fluoro-3,4-dihydro-1H- isoquinoline-2-carboxylic acid benzyl ester 197 8-(5-Carboxymethyl-2-propoxy- C28H28NO5F 1.18 478.3 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 198 8-(5-Carboxymethyl-2-isobutoxy- C29H30NO5F 1.24 492.3 phenyl)-5-fluoro-3,4-dihydro-1H- 491.21 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 199 8-[5-Carboxymethyl-2-(2-methoxy- C28H28NO6F 1.06 494.3 ethoxy)-phenyl]-5-fluoro-3,4- 493.19 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester

Saponification

Method A: To a solution of {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid ethyl ester (enantiomer 1) (73 mg, 0.14 mmol, 1 eq.) in DMF (0.5 mL), 2M aq. NaOH soln. (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (0.3 mL) and then purified by prep. HPLC (column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 18 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 1 as starting material.

TABLE 18 Formula t_(R) [min] MW LC-MS LC-MS Method Compound of Starting ester of Method MS-data Example Formula (I) Structure 1 t_(R) [min] m/z [M + H]⁺ 200 {4-[2-(2-Chroman-4- {4-[2-(2-Chroman-4-yl- C29H28NO5F 1.09 yl-acetyl)-5-fluoro- acetyl)-5-fluoro-1,2,3,4- 489.20 LC-MS 1FA 1,2,3,4-tetrahydro- tetrahydro-isoquinolin-8- LC-MS 5 490.4 isoquinolin-8-yl]-3- yl]-3-methoxy-phenyl}- 12.26 methoxy-phenyl}- acetic acid ethyl ester acetic acid (enantiomer 1) (enantiomer 1) 201 {4-[2-(2-Chroman-4- {4-[2-(2-Chroman-4-yl- C29H28NO5F 1.09 yl-acetyl)-5-fluoro- acetyl)-5-fluoro-1,2,3,4- 489.20 LC-MS 1FA 1,2,3,4-tetrahydro- tetrahydro-isoquinolin-8- LC-MS 5 490.3 isoquinolin-8-yl]-3- yl]-3-methoxy-phenyl}- 15.02 methoxy-phenyl}- acetic acid ethyl ester acetic acid (enantiomer 2) (enantiomer 2) 202 8-[4-(1-Carboxy- 5-Fluoro-8-[2-methoxy-4- C27H26NO6F 1.19 ethoxy)-2-methoxy- (1-methoxycarbonyl- 479.17 LC-MS 1FA phenyl]-5-fluoro-3,4- ethoxy)-phenyl]-3,4- LC-MS 6 480.4 dihydro-1H- dihydro-1H-isoquinoline- 7.59 isoquinoline-2- 2-carboxylic acid benzyl carboxylic acid benzyl ester (enantiomer 2) ester (enantiomer 2) 203 {4-Ethoxy-3-[5-fluoro- {4-Ethoxy-3-[5-fluoro-2- C28H29N2O4F 0.82 2-(3-pyridin-2-yl- (3-pyridin-2-yl-butyryl)- 476.21 LC-MS 1FA butyryl)-1,2,3,4- 1,2,3,4-tetrahydro- LC-MS 7 477.4 tetrahydro-isoquinolin- isoquinolin-8-yl]-phenyl}- 11.68 8-yl]-phenyl}-acetic acetic acid ethyl ester acid (enantiomer 1) (enantiomer 1) 204 {4-Ethoxy-3-[5-fluoro- {4-Ethoxy-3-[5-fluoro-2- C28H29N2O4F 0.82 2-(3-pyridin-2-yl- (3-pyridin-2-yl-butyryl)- 476.21 LC-MS 1FA butyryl)-1,2,3,4- 1,2,3,4-tetrahydro- LC-MS 7 477.4 tetrahydro-isoquinolin- isoquinolin-8-yl]-phenyl}- 14.51 8-yl]-phenyl}-acetic acetic acid ethyl ester acid (enantiomer 2) (enantiomer 2) 205 {3-Ethoxy-4-[5-fluoro- {3-Ethoxy-4-[5-fluoro-2- C30H30NO5F 1.13 2-(2-isochroman-1-yl- (2-isochroman-1-yl- 503.21 LC-MS 1FA acetyl)-1,2,3,4- acetyl)-1,2,3,4- LC-MS 8 504.4 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 11.99 8-yl]-phenyl}-acetic yl]-phenyl}-acetic acid acid (enantiomer 1) ethyl ester (enantiomer 1) 206 {3-Ethoxy-4-[5-fluoro- {3-Ethoxy-4-[5-fluoro-2- C30H30NO5F 1.13 2-(2-isochroman-1-yl- (2-isochroman-1-yl- 503.21 LC-MS 1FA acetyl)-1,2,3,4- acetyl)-1,2,3,4- LC-MS 8 504.4 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 14.04 8-yl]-phenyl}-acetic yl]-phenyl}-acetic acid acid (enantiomer 2) ethyl ester (enantiomer 2) 207 {3-[2-(2-2,3-Dihydro- {3-[2-(2-2,3-Dihydro- C29H28NO5F 1.13 benzofuran-3-yl- benzofuran-3-yl-acetyl)- 489.20 LC-MS 1FA acetyl)-5-fluoro- 5-fluoro-1,2,3,4- LC-MS 9 490.4 1,2,3,4-tetrahydro- tetrahydro-isoquinolin-8- 10.37 isoquinolin-8-yl]-4- yl]-4-ethoxy-phenyl}- ethoxy-phenyl}-acetic acetic acid ethyl ester acid (enantiomer 1) (enantiomer 1) 208 {3-[2-(2-2,3-Dihydro- {3-[2-(2-2,3-Dihydro- C29H28NO5F 1.13 benzofuran-3-yl- benzofuran-3-yl-acetyl)- 489.20 LC-MS 1FA acetyl)-5-fluoro- 5-fluoro-1,2,3,4- LC-MS 9 490.4 1,2,3,4-tetrahydro- tetrahydro-isoquinolin-8- 16.38 isoquinolin-8-yl]-4- yl]-4-ethoxy-phenyl}- ethoxy-phenyl}-acetic acetic acid ethyl ester acid (enantiomer 2) (enantiomer 2) 209 {4-Ethoxy-3-[5-fluoro- {4-Ethoxy-3-[5-fluoro-2- C30H30NO5F 1.10 2-(2-isochroman-4-yl- (2-isochroman-4-yl- 503.21 LC-MS 1FA acetyl)-1,2,3,4- acetyl)-1,2,3,4- LC-MS 10 504.4 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 10.74 8-yl]-phenyl}-acetic yl]-phenyl}-acetic acid acid (enantiomer 1) ethyl ester (enantiomer 1) 210 {4-Ethoxy-3-[5-fluoro- {4-Ethoxy-3-[5-fluoro-2- C30H30NO5F 1.10 2-(2-isochroman-4-yl- (2-isochroman-4-yl- 503.21 LC-MS 1FA acetyl)-1,2,3,4- acetyl)-1,2,3,4- LC-MS 10 504.4 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 16.09 8-yl]-phenyl}-acetic yl]-phenyl}-acetic acid acid (enantiomer 2) ethyl ester (enantiomer 2) 211 (4-Ethoxy-3-{5-fluoro- (4-Ethoxy-3-{5-fluoro-2- C29H29NO4F2 1.17 2-[3-(4-fluoro-phenyl)- [3-(4-fluoro-phenyl)- 493.21 LC-MS 1FA butyryl]-1,2,3,4- butyryl]-1,2,3,4- LC-MS 11 494.3 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 25.22 8-yl}-phenyl)-acetic yl}-phenyl)-acetic acid acid (enantiomer 1) ethyl ester (enantiomer 1) 212 (4-Ethoxy-3-{5-fluoro- (4-Ethoxy-3-{5-fluoro-2- C29H29NO4F2 1.17 2-[3-(4-fluoro-phenyl)- [3-(4-fluoro-phenyl)- 493.21 LC-MS 1FA butyryl]-1,2,3,4- butyryl]-1,2,3,4- LC-MS 11 494.3 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 27.93 8-yl}-phenyl)-acetic yl}-phenyl)-acetic acid acid (enantiomer 2) ethyl ester (enantiomer 2) 213 {4-Ethoxy-3-[5-fluoro- {4-Ethoxy-3-[5-fluoro-2- C29H30NO4F 1.17 2-(2-methyl-3-phenyl- (2-methyl-3-phenyl- 475.22 LC-MS 1FA propionyl)-1,2,3,4- propionyl)-1,2,3,4- LC-MS 12 476.4 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 27.19 8-yl]-phenyl}-acetic yl]-phenyl}-acetic acid acid (enantiomer 1) ethyl ester (enantiomer 1) 214 {4-Ethoxy-3-[5-fluoro- {4-Ethoxy-3-[5-fluoro-2- C29H30NO4F 1.17 2-(2-methyl-3-phenyl- (2-methyl-3-phenyl- 475.22 LC-MS 1FA propionyl)-1,2,3,4- propionyl)-1,2,3,4- LC-MS 12 476.3 tetrahydro-isoquinolin- tetrahydro-isoquinolin-8- 31.51 8-yl]-phenyl}-acetic yl]-phenyl}-acetic acid acid (enantiomer 2) ethyl ester (enantiomer 2)

Method B: TFA (0.49 mL) was slowly added to an ice-cooled solution of 8-(5-tert-butoxycarbonylmethyl-2-propyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (110 mg, 0.21 mmol, 1 eq.) in DCM (0.55 mL). The reaction mixture was stirred at r.t. for 30 min. The mixture was concentrated in vacuo without heating and the residue was redissolved in MeCN (0.8 mL). The crude mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a pale yellow oil.

Listed in Table 19 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 1 as starting material.

TABLE 19 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 215 8-(5-Carboxymethyl-2-propyl- C28H28NO4F 1.31 462.4 phenyl)-5-fluoro-3,4-dihydro-1H- 461.20 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 216 8-(4-Carboxymethyl-2-isopropyl- C28H28NO4F 1.29 462.3 phenyl)-5-fluoro-3,4-dihydro-1H- 461.20 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 217 8-(4-Carboxymethyl-2-isopropoxy- C28H28NO5F 1.24 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester

Example 218 8-(4-Carboxymethyl-2,6-dimethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H26NO6F, MW=479.17)

To a solution of 8-(4-ethoxycarbonylmethyl-2,6-dimethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (9.5 mg, 0.02 mmol, 1 eq.) in DMF (0.1 mL), 2M aq. NaOH soln. (68 μL) was added. The solution was stirred at r.t. for 18 hours. Formic acid was added (0.1 mL). The resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 19×30 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

LC-MS 1TFA: t_(R)=1.13 min; [M+H]⁺=480.3

Amide Coupling and Subsequent Saponification

Method A: To a solution of (±)-indan-1-yl-acetic acid (22 mg, 0.12 mmol, 1.2 eq.) in DCM/DMF 1:1 (1.00 mL), TBTU (39 mg, 0.12 mmol, 1.2 eq.) and Si-DEA (238 mg, 0.30 mmol, 3.0 eq.) were added in sequence. The mixture was stirred at r.t. for 1 hour. A solution of [4-ethoxy-3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (36 mg, 0.10 mmol, 1.0 eq.) in DMF (0.25 mL) was added and the resulting mixture was stirred at r.t. for 1 hour. The mixture was filtered, the solid rinsed with DCM (3 mL), and the filtrate was concentrated in vacuo. To a solution of the residue in THF (0.5 mL), 1M aq. NaOH (1.0 mL) was added. The mixture was stirred at r.t. for 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

Listed in Table 20 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 20 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 219 (±)-{4-Ethoxy-3-[5-fluoro-2-(2- C30H30NO4F 1.19 488.4 indan-1-yl-acetyl)-1,2,3,4- 487.22 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 220 {4-Ethoxy-3-[5-fluoro-2-((1R,2R)- C29H28NO4F 1.16 474.4 2-phenyl-cyclopropanecarbonyl)- 473.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-phenyl}-acetic acid 221 {4-Ethoxy-3-[5-fluoro-2-((R)-3- C29H30NO4F 1.16 476.4 phenyl-butyryl)-1,2,3,4-tetrahydro- 475.22 LC-MS 1FA isoquinolin-8-yl]-phenyl}-acetic acid 222 (4-Ethoxy-3-{5-fluoro-2-[2-(1- C30H30NO4F 1.16 488.4 phenyl-cyclopropyl)-acetyl]- 487.22 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl}-phenyl)-acetic acid 223 (4-Ethoxy-3-{5-fluoro-2-[3-(4- C30H31NO4F2 1.19 508.4 fluoro-phenyl)-3-methyl-butyryl]- 507.22 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl}-phenyl)-acetic acid 224 (±)-{4-Ethoxy-3-[5-fluoro-2-(2- C30H30NO5F 1.12 504.4 isochroman-1-yl-acetyl)-1,2,3,4- 503.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 225 {4-Ethoxy-3-[5-fluoro-2-(3-methyl- C30H32NO4F 1.19 490.4 3-phenyl-butyryl)-1,2,3,4- 489.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 226 (±)-{3-[2-(2-Chroman-4-yl-acetyl)- C30H30NO5F 1.13 504.4 5-fluoro-1,2,3,4-tetrahydro- 503.21 LC-MS 1FA isoquinolin-8-yl]-4-ethoxy-phenyl}- acetic acid 227 (±)-{3-[2-(2-2,3-Dihydro- C29H28NO5F 1.13 490.4 benzofuran-3-yl-acetyl)-5-fluoro- 489.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-4-ethoxy-phenyl}-acetic acid 228 (±)-{4-Ethoxy-3-[5-fluoro-2-(2- C30H30NO5F 1.29 504.3 isochroman-4-yl-acetyl)-1,2,3,4- 503.21 LC-MS 13 tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 229 (±)-{3-Ethoxy-4-[5-fluoro-2-(2- C30H30NO5F 1.13 504.4 isochroman-1-yl-acetyl)-1,2,3,4- 503.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 230 (3-Ethoxy-4-{5-fluoro-2-[2-(1- C30H30NO4F 1.18 488.4 phenyl-cyclopropyl)-acetyl]- 487.22 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl}-phenyl)-acetic acid 231 {3-Ethoxy-4-[5-fluoro-2-((1R,2R)- C29H28NO4F 1.17 474.4 2-phenyl-cyclopropanecarbonyl)- 473.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-phenyl}-acetic acid 232 (±)-{3-Ethoxy-4-[5-fluoro-2-(2- C30H30NO5F 1.11 504.4 isochroman-4-yl-acetyl)-1,2,3,4- 503.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 233 (±)-{3-Ethoxy-4-[5-fluoro-2-(2- C30H30NO4F 1.20 488.4 indan-1-yl-acetyl)-1,2,3,4- 487.22 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 234 {3-Ethoxy-4-[5-fluoro-2-((R)-3- C29H30NO4F 1.17 476.4 phenyl-butyryl)-1,2,3,4-tetrahydro- 475.22 LC-MS 1FA isoquinolin-8-yl]-phenyl}-acetic acid 235 (±)-{4-[2-(2-2,3-Dihydro- C29H28NO5F 1.14 490.4 benzofuran-3-yl-acetyl)-5-fluoro- 489.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-3-ethoxy-phenyl}-acetic acid 236 (±)-{4-[2-(2-Chroman-4-yl-acetyl)- C30H30NO5F 1.14 504.3 5-fluoro-1,2,3,4-tetrahydro- 503.21 LC-MS 1FA isoquinolin-8-yl]-3-ethoxy-phenyl}- acetic acid 237 (3-Ethoxy-4-{5-fluoro-2-[3-(4- C30H31NO4F2 1.20 508.4 fluoro-phenyl)-3-methyl-butyryl]- 507.22 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl}-phenyl)-acetic acid 238 {3-Ethoxy-4-[5-fluoro-2-(3-methyl- C30H32NO4F 1.21 490.4 3-phenyl-butyryl)-1,2,3,4- 489.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid

Method B: A solution of (±)-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid (22 mg, 0.12 mmol, 1.2 eq.) and [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (34 mg, 0.10 mmol, 1.0 eq.) in DMF (1.2 mL) was treated with 4-(dimethylamino)pyridine (37 mg, 0.30 mmol, 3.0 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol, 1.5 eq) and the resulting solution was stirred at r.t. for 18 hours. 1M aq. NaOH soln. (1.0 mL) was added. The solution was stirred at r.t. during 2 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 21 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 21 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 239 (±)-(3-{5-Fluoro-2-[2-(1-methyl- C31H32NO4F 1.18 502.4 1,2,3,4-tetrahydro-naphthalen-1-yl)- 501.23 LC-MS 1FA acetyl]-1,2,3,4-tetrahydro- isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 240 (±)-(3-{2-[2-(2,2-Dimethyl-chroman- C31H32NO5F 1.16 518.4 4-yl)-acetyl]-5-fluoro-1,2,3,4- 517.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 241 (±)-{3-[5-Fluoro-2-(8-methoxy- C30H30NO5F 1.14 504.4 1,2,3,4-tetrahydro-naphthalene-2- 503.21 LC-MS 1FA carbonyl)-1,2,3,4-tetrahydro- isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 242 (±)-{3-[2-(2-Chroman-3-yl-acetyl)-5- C29H28NO5F 1.10 490.3 fluoro-1,2,3,4-tetrahydro- 489.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 243 (±)-(3-{5-Fluoro-2-[2-(7-fluoro- C29H27NO5F2 1.10 508.4 chroman-4-yl)-acetyl]-1,2,3,4- 507.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 244 (±)-(3-{5-Fluoro-2-[2-(6-fluoro- C29H27NO5F2 1.09 508.3 chroman-4-yl)-acetyl]-1,2,3,4- 507.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 245 (±)-{3-[2-(3-Cyclopropyl-butyryl)-5- C25H28NO4F 1.06 426.4 fluoro-1,2,3,4-tetrahydro- 425.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 246 (±)-(3-{5-Fluoro-2-[2-(8-fluoro- C29H27NO5F2 1.08 508.3 chroman-4-yl)-acetyl]-1,2,3,4- 507.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 247 (±)-{3-[5-Fluoro-2-(2-5,6,7,8- C29H29N2O4F 0.74 489.4 tetrahydro-isoquinolin-8-yl-acetyl)- 488.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid hydrochloride 248 (±)-(3-{5-Fluoro-2-[3-(6-methoxy- C28H29N2O5F 1.08 493.4 pyridin-2-yl)-butyryl]-1,2,3,4- 492.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid hydrochloride 249 (±)-(3-{5-Fluoro-2-[3-(6-methyl- C28H29N2O4F 0.74 477.4 pyridin-2-yl)-butyryl]-1,2,3,4- 476.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid hydrochloride 250 (3-{5-Fluoro-2-[2-(1-phenyl- C30H30NO4F 1.16 488.4 cyclobutyl)-acetyl]-1,2,3,4- 487.22 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 251 [3-(5-Fluoro-2-{2-[1-(4-fluoro- C30H29NO4F2 1.16 506.4 phenyl)-cyclobutyl]-acetyl}-1,2,3,4- 505.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl)-4- methoxy-phenyl]-acetic acid 252 (3-{5-Fluoro-2-[3-(3-fluoro-phenyl)- C29H29NO4F2 1.14 494.4 3-methyl-butyryl]-1,2,3,4-tetrahydro- 493.21 LC-MS 1FA isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 253 (±)-{3-[2-(2-{[(4-Chloro-phenyl)- C34H32N2O4ClF 1.00 587.3 phenyl-methyl]-methyl-amino}- 586.20 LC-MS 1TFA acetyl)-5-fluoro-1,2,3,4-tetrahydro- isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 254 {3-[2-(2-Cyclopropyl-acetyl)-5- C23H24NO4F 0.97 398.4 fluoro-1,2,3,4-tetrahydro- 397.17 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 255 {3-[5-Fluoro-2-((R)-2-phenyl- C27H26NO4F 1.07 448.4 propionyl)-1,2,3,4-tetrahydro- 447.19 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 256 (±)-{3-[5-Fluoro-2-(3-hydroxy-3- C28H28NO5F 1.04 478.4 phenyl-butyryl)-1,2,3,4-tetrahydro- 477.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 257 (±)-{3-[5-Fluoro-2-(2-isochroman-1- C29H28NO5F 1.06 490.4 yl-acetyl)-1,2,3,4-tetrahydro- 489.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 258 (3-{5-Fluoro-2-[2-(1-phenyl- C29H28NO4F 1.11 474.4 cyclopropyl)-acetyl]-1,2,3,4- 473.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 259 (±)-(3-{5-Fluoro-2-[2-(2-methyl- C30H31N2O4F 0.84 503.4 1,2,3,4-tetrahydro-isoquinolin-1-yl)- 502.23 LC-MS 1TFA acetyl]-1,2,3,4-tetrahydro- isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 260 (±)-{3-[5-Fluoro-2-(2-1,2,3,4- C30H30NO4F 1.17 488.4 tetrahydro-naphthalen-2-yl-acetyl)- 487.22 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid 261 (±)-{3-[5-Fluoro-2-(2-indan-1-yl- C29H28NO4F 1.13 474.4 acetyl)-1,2,3,4-tetrahydro- 473.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 262 (±)-{3-[2-(2-Chroman-4-yl-acetyl)-5- C29H28NO5F 1.07 490.4 fluoro-1,2,3,4-tetrahydro- 489.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 263 (±)-{3-[5-Fluoro-2-(2-1,2,3,4- C30H30NO4F 1.16 488.4 tetrahydro-naphthalen-1-yl-acetyl)- 487.22 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid 264 (±)-{3-[5-Fluoro-2-(4-methyl-3- C30H32NO4F 1.18 490.4 phenyl-pentanoyl)-1,2,3,4- 489.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 265 (±)-{3-[5-Fluoro-2-(3-pyridin-2-yl- C27H27N2O4F 0.76 463.4 butyryl)-1,2,3,4-tetrahydro- 462.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 266 (±)-{3-[5-Fluoro-2-(3-pyridin-3-yl- C27H27N2O4F 0.73 463.4 butyryl)-1,2,3,4-tetrahydro- 462.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid formiate 267 (±)-{3-[5-Fluoro-2-(3-pyridin-4-yl- C27H27N2O4F 0.71 463.4 butyryl)-1,2,3,4-tetrahydro- 462.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid formiate 268 (±)-{3-[5-Fluoro-2-(3-phenyl- C29H30NO4F 1.14 476.4 pentanoyl)-1,2,3,4-tetrahydro- 475.22 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 269 {3-[5-Fluoro-2-((R)-1,2,3,4- C29H28NO4F 1.11 474.4 tetrahydro-naphthalene-1-carbonyl)- 473.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid 270 (±)-{3-[2-(2-2,3-Dihydro-benzofuran- C28H26NO5F 1.07 476.4 3-yl-acetyl)-5-fluoro-1,2,3,4- 475.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 271 (±)-{3-[5-Fluoro-2-(2-isochroman-4- C29H28NO5F 1.04 490.4 yl-acetyl)-1,2,3,4-tetrahydro- 489.20 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 272 (±)-{3-[2-(Chroman-4-carbonyl)-5- C28H26NO5F 1.04 476.4 fluoro-1,2,3,4-tetrahydro- 475.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 273 (±)-{3-[5-Fluoro-2-(isochroman-1- C28H26NO5F 1.04 476.4 carbonyl)-1,2,3,4-tetrahydro- 475.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 274 (±)-{3-[5-Fluoro-2-(isochroman-3- C28H26NO5F 1.07 476.4 carbonyl)-1,2,3,4-tetrahydro- 475.18 LC-MS 1FA isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 275 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(3- C30H29NO4F2 1.17 506.4 fluoro-phenyl)-cyclopropyl]-acetyl}- 505.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl)- phenyl]-acetic acid 276 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(2- C30H29NO4F2 1.16 506.4 fluoro-phenyl)-cyclopropyl]-acetyl}- 505.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl)- phenyl]-acetic acid 277 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(4- C30H29NO4F2 1.16 506.4 fluoro-phenyl)-cyclopropyl]-acetyl}- 505.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl)- phenyl]-acetic acid 278 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(4- C29H29NO4F2 1.16 494.4 fluoro-phenyl)-butyryl]-1,2,3,4- 493.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 279 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(3- C29H29NO4F2 1.16 494.4 fluoro-phenyl)-butyryl]-1,2,3,4- 493.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 280 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(2- C29H29NO4F2 1.17 494.4 fluoro-phenyl)-butyryl]-1,2,3,4- 493.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 281 (±)-{4-Ethoxy-3-[5-fluoro-2-(3- C27H28N3O4F 0.98 478.4 pyrazin-2-yl-butyryl)-1,2,3,4- 477.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 282 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(2- C30H32NO5F 1.18 506.4 methoxy-phenyl)-butyryl]-1,2,3,4- 505.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 283 (±)-{4-Ethoxy-3-[5-fluoro-2-(3- C26H27N2O4FS 1.03 483.3 thiazol-2-yl-butyryl)-1,2,3,4- 482.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 284 (±)-(3-{2-[2-(2,2-Dimethyl-3,4- C31H33N2O5F 0.95 533.4 dihydro-2H-pyrano[2,3-b]pyridin-4- 532.24 LC-MS 1FA yl)-acetyl]-5-fluoro-1,2,3,4- tetrahydro-isoquinolin-8-yl}-4- ethoxy-phenyl)-acetic acid 285 (±)-[4-[2-(2-Chroman-4-yl-acetyl)-5- C30H27NO5F4 1.17 558.3 fluoro-1,2,3,4-tetrahydro- 557.18 LC-MS 1FA isoquinolin-8-yl]-3-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 286 [4-[5-Fluoro-2-(3-methyl-3-phenyl- C30H29NO4F4 1.23 544.4 butyryl)-1,2,3,4-tetrahydro- 543.20 LC-MS 1FA isoquinolin-8-yl]-3-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 287 [4-[5-Fluoro-2-((S)-3-phenyl- C29H27NO4F4 1.19 530.3 butyryl)-1,2,3,4-tetrahydro- 529.19 LC-MS 1FA isoquinolin-8-yl]-3-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 288 (±)-[4-[5-Fluoro-2-(3-pyridin-2-yl- C28H26N2O4F4 0.86 531.4 butyryl)-1,2,3,4-tetrahydro- 530.18 LC-MS 1FA isoquinolin-8-yl]-3-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 289 [4-[5-Fluoro-2-((1R,2R)-2-phenyl- C29H25NO4F4 1.19 528.3 cyclopropanecarbonyl)-1,2,3,4- 527.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-3-(2,2,2- trifluoro-ethoxy)-phenyl]-acetic acid 290 (±)-{3-[2-(2-Chroman-4-yl-acetyl)-5- C31H32NO5F 1.18 518.4 fluoro-1,2,3,4-tetrahydro- 517.23 LC-MS 1FA isoquinolin-8-yl]-4-isopropoxy- phenyl}-acetic acid 291 {3-[5-Fluoro-2-(3-methyl-3-phenyl- C31H34NO4F 1.25 504.4 butyryl)-1,2,3,4-tetrahydro- 503.25 LC-MS 1FA isoquinolin-8-yl]-4-isopropoxy- phenyl}-acetic acid 292 {3-[5-Fluoro-2-((R)-3-phenyl- C30H32NO4F 1.21 490.4 butyryl)-1,2,3,4-tetrahydro- 489.23 LC-MS 1FA isoquinolin-8-yl]-4-isopropoxy- phenyl}-acetic acid 293 (±)-{3-[5-Fluoro-2-(3-pyridin-2-yl- C29H31N2O4F 0.88 491.4 butyryl)-1,2,3,4-tetrahydro- 490.23 LC-MS 1FA isoquinolin-8-yl]-4-isopropoxy- phenyl}-acetic acid 294 (±)-(3-{5-Fluoro-2-[3-(6-methyl- C30H33N2O4F 0.83 505.4 pyridin-2-yl)-butyryl]-1,2,3,4- 504.24 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- isopropoxy-phenyl)-acetic acid 295 (3-{5-Fluoro-2-[3-(6-methyl-pyridin- C29H31N2O4F 0.81 491.4 2-yl)-propionyl]-1,2,3,4-tetrahydro- 490.23 LC-MS 1FA isoquinolin-8-yl}-4-isopropoxy- phenyl)-acetic acid 296 (±)-{3-[5-Fluoro-2-(2-isochroman-4- C31H32NO5F 1.15 518.4 yl-acetyl)-1,2,3,4-tetrahydro- 517.23 LC-MS 1FA isoquinolin-8-yl]-4-isopropoxy- phenyl}-acetic acid 297 (±)-{3-[5-Fluoro-2-(2-isochroman-1- C31H32NO5F 1.17 518.4 yl-acetyl)-1,2,3,4-tetrahydro- 517.23 LC-MS 1FA isoquinolin-8-yl]-4-isopropoxy- phenyl}-acetic acid 298 (±)-{3-[2-(2-2,3-Dihydro-benzofuran- C30H30NO5F 1.18 504.4 3-yl-acetyl)-5-fluoro-1,2,3,4- 503.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- isopropoxy-phenyl}-acetic acid 299 (±)-[3-[2-(2-Chroman-4-yl-acetyl)-5- C30H27NO5F4 1.15 558.4 fluoro-1,2,3,4-tetrahydro- 557.18 LC-MS 1FA isoquinolin-8-yl]-4-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 300 [3-[5-Fluoro-2-(3-methyl-3-phenyl- C30H29NO4F4 1.21 544.4 butyryl)-1,2,3,4-tetrahydro- 543.20 LC-MS 1FA isoquinolin-8-yl]-4-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 301 [3-[5-Fluoro-2-((R)-3-phenyl- C29H27NO4F4 1.17 530.4 butyryl)-1,2,3,4-tetrahydro- 529.19 LC-MS 1FA isoquinolin-8-yl]-4-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 302 (±)-[3-[5-Fluoro-2-(3-pyridin-2-yl- C28H26N2O4F4 0.86 531.3 butyryl)-1,2,3,4-tetrahydro- 530.18 LC-MS 1FA isoquinolin-8-yl]-4-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 303 (±)-[3-{5-Fluoro-2-[3-(6-methyl- C29H28N2O4F4 0.82 545.4 pyridin-2-yl)-butyryl]-1,2,3,4- 544.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4-(2,2,2- trifluoro-ethoxy)-phenyl]-acetic acid 304 [3-{5-Fluoro-2-[3-(6-methyl-pyridin- C28H26N2O4F4 0.79 531.4 2-yl)-propionyl]-1,2,3,4-tetrahydro- 530.18 LC-MS 1FA isoquinolin-8-yl}-4-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 305 (±)-[3-[5-Fluoro-2-(2-isochroman-4- C30H27NO5F4 1.12 558.3 yl-acetyl)-1,2,3,4-tetrahydro- 557.18 LC-MS 1FA isoquinolin-8-yl]-4-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 306 (±)-[3-[5-Fluoro-2-(2-isochroman-1- C30H27NO5F4 1.14 558.3 yl-acetyl)-1,2,3,4-tetrahydro- 557.18 LC-MS 1FA isoquinolin-8-yl]-4-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 307 (±)-[3-[2-(2-2,3-Dihydro-benzofuran- C29H25NO5F4 1.15 544.3 3-yl-acetyl)-5-fluoro-1,2,3,4- 543.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4-(2,2,2- trifluoro-ethoxy)-phenyl]-acetic acid 308 (±)-{4-Ethoxy-3-[5-fluoro-2-(3- C29H31N2O4F 0.86 491.4 pyridin-2-yl-pentanoyl)-1,2,3,4- 490.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 309 (4-Ethoxy-3-{5-fluoro-2-[3-(3- C28H29N2O5F 0.83 493.4 methoxy-pyridin-2-yl)-propionyl]- 492.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 310 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro- C28H27NO4F2 1.13 480.4 phenyl)-propionyl]-1,2,3,4- 479.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 311 (4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro- C28H27NO4F2 1.14 480.4 phenyl)-propionyl]-1,2,3,4- 479.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 312 (4-Ethoxy-3-{5-fluoro-2-[3-(2-fluoro- C28H27NO4F2 1.14 480.4 phenyl)-propionyl]-1,2,3,4- 479.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 313 (±)-{3-Ethoxy-4-[5-fluoro-2-(3- C29H31N2O4F 0.85 491.4 pyridin-2-yl-pentanoyl)-1,2,3,4- 490.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 314 (3-Ethoxy-4-{5-fluoro-2-[3-(3- C28H29N2O5F 0.83 493.4 methoxy-pyridin-2-yl)-propionyl]- 492.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 315 (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro- C28H27NO4F2 1.14 480.4 phenyl)-propionyl]-1,2,3,4- 479.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 316 (3-Ethoxy-4-{5-fluoro-2-[3-(3-fluoro- C28H27NO4F2 1.15 480.3 phenyl)-propionyl]-1,2,3,4- 479.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 317 (3-Ethoxy-4-{5-fluoro-2-[3-(2-fluoro- C28H27NO4F2 1.15 480.4 phenyl)-propionyl]-1,2,3,4- 479.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 318 (±)-{3-[2-(3-Cyclopropyl-3-pyridin-2- C30H31N2O4F 0.89 503.4 yl-propionyl)-5-fluoro-1,2,3,4- 502.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- ethoxy-phenyl}-acetic acid 319 (±)-{4-[2-(3-Cyclopropyl-3-pyridin-2- C30H31N2O4F 0.88 503.4 yl-propionyl)-5-fluoro-1,2,3,4- 502.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-3- ethoxy-phenyl}-acetic acid 320 (±)-(3-Ethoxy-4-{5-fluoro-2-[3-(6- C29H31N2O4F 0.79 491.4 methyl-pyridin-2-yl)-butyryl]-1,2,3,4- 490.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 321 (3-Ethoxy-4-{5-fluoro-2-[3-(6- C28H29N2O4F 0.76 477.4 methyl-pyridin-2-yl)-propionyl]- 476.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 322 (±)-{3-Ethoxy-4-[5-fluoro-2-(trans-2- C28H27N2O4F 0.93 475.4 pyridin-2-yl-cyclopropanecarbonyl)- 474.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 323 (±)-(4-{2-[2-(2,2-Dimethyl-chroman- C32H34NO5F 1.23 532.4 4-yl)-acetyl]-5-fluoro-1,2,3,4- 531.24 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-3- ethoxy-phenyl)-acetic acid 324 (±)-{4-[2-(2-Chroman-3-yl-acetyl)-5- C30H30NO5F 1.17 504.4 fluoro-1,2,3,4-tetrahydro- 503.21 LC-MS 1FA isoquinolin-8-yl]-3-ethoxy-phenyl}- acetic acid 325 (±)-{3-Ethoxy-4-[5-fluoro-2-(8- C31H32NO5F 1.21 518.4 methoxy-1,2,3,4-tetrahydro- 517.23 LC-MS 1FA naphthalene-2-carbonyl)-1,2,3,4- tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 326 (±)-(3-Ethoxy-4-{5-fluoro-2-[2-(1- C32H34NO4F 1.25 516.5 methyl-1,2,3,4-tetrahydro- 515.25 LC-MS 1FA naphthalen-1-yl)-acetyl]-1,2,3,4- tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 327 (±)-(3-Ethoxy-4-{5-fluoro-2-[2-(7- C30H29NO5F2 1.16 522.3 fluoro-chroman-4-yl)-acetyl]-1,2,3,4- 521.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 328 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(6- C29H31N2O4F 0.79 491.4 methyl-pyridin-2-yl)-butyryl]-1,2,3,4- 490.23 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 329 (4-Ethoxy-3-{5-fluoro-2-[3-(6- C28H29N2O4F 0.76 477.4 methyl-pyridin-2-yl)-propionyl]- 476.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 330 (±)-{4-Ethoxy-3-[5-fluoro-2-(trans-2- C28H27N2O4F 0.95 475.4 pyridin-2-yl-cyclopropanecarbonyl)- 474.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 331 (±)-(3-{2-[2-(2,2-Dimethyl-chroman- C32H34NO5F 1.22 532.4 4-yl)-acetyl]-5-fluoro-1,2,3,4- 531.24 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-4- ethoxy-phenyl)-acetic acid 332 (±)-{3-[2-(2-Chroman-3-yl-acetyl)-5- C30H30NO5F 1.16 504.3 fluoro-1,2,3,4-tetrahydro- 503.21 LC-MS 1FA isoquinolin-8-yl]-4-ethoxy-phenyl}- acetic acid 333 (±)-{4-Ethoxy-3-[5-fluoro-2-(8- C31H32NO5F 1.20 518.4 methoxy-1,2,3,4-tetrahydro- 517.23 LC-MS 1FA naphthalene-2-carbonyl)-1,2,3,4- tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 334 (±)-(4-Ethoxy-3-{5-fluoro-2-[2-(1- C32H34NO4F 1.24 516.4 methyl-1,2,3,4-tetrahydro- 515.25 LC-MS 1FA naphthalen-1-yl)-acetyl]-1,2,3,4- tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 335 (±)-(4-Ethoxy-3-{5-fluoro-2-[2-(7- C30H29NO5F2 1.15 522.4 fluoro-chroman-4-yl)-acetyl]-1,2,3,4- 521.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl}-phenyl)- acetic acid 336 {4-Ethoxy-3-[5-fluoro-2-((E)-3- C27H25N2O4F 1.01 461.4 pyridin-2-yl-acryloyl)-1,2,3,4- 460.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 337 (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1- C26H26N3O4F 0.98 464.4 methyl-1H-pyrazol-3-yl)-acryloyl]- 463.19 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 338 {3-Ethoxy-4-[5-fluoro-2-((E)-3- C27H25N2O4F 0.99 461.4 pyridin-2-yl-acryloyl)-1,2,3,4- 460.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 339 (3-Ethoxy-4-{5-fluoro-2-[(E)-3-(1- C26H26N3O4F 0.98 464.4 methyl-1H-pyrazol-4-yl)-acryloyl]- 463.19 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 340 {4-Ethoxy-3-[5-fluoro-2-(2-pyridin-2- C26H25N2O4F 0.83 449.4 yl-acetyl)-1,2,3,4-tetrahydro- 448.18 LC-MS 1FA isoquinolin-8-yl]-phenyl}-acetic acid 341 (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1- C26H26N3O4F 0.98 464.4 methyl-1H-pyrazol-4-yl)-acryloyl]- 463.19 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 342 {3-Ethoxy-4-[5-fluoro-2-(2-pyridin-2- C26H25N2O4F 0.84 449.4 yl-acetyl)-1,2,3,4-tetrahydro- 448.18 LC-MS 1FA isoquinolin-8-yl]-phenyl}-acetic acid 343 (±)-{3-[5-Fluoro-2-(2-methyl-3- C27H27N2O4F 0.73 463.4 pyridin-3-yl-propionyl)-1,2,3,4- 462.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 344 (±)-{3-Ethoxy-4-[5-fluoro-2-(3- C28H29N2O4F 0.82 477.4 pyridin-2-yl-butyryl)-1,2,3,4- 476.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 345 (±)-{4-Ethoxy-3-[5-fluoro-2-(3- C28H29N2O4F 0.82 477.4 pyridin-2-yl-butyryl)-1,2,3,4- 476.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-phenyl}- acetic acid 346 (±)-{4-[5-Fluoro-2-(3-pyridin-2-yl- C29H31N2O4F 0.87 491.4 butyryl)-1,2,3,4-tetrahydro- 490.23 LC-MS 1FA isoquinolin-8-yl]-3-isopropoxy- phenyl}-acetic acid 347 [4-[5-Fluoro-2-((R)-3-phenyl- C29H27NO4F4 1.19 530.4 butyryl)-1,2,3,4-tetrahydro- 529.19 LC-MS 1FA isoquinolin-8-yl]-3-(2,2,2-trifluoro- ethoxy)-phenyl]-acetic acid 348 {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2- C27H27N2O4F 0.78 463.4 yl-propionyl)-1,2,3,4-tetrahydro- 462.20 LC-MS 1FA isoquinolin-8-yl]-phenyl}-acetic acid 349 {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2- C27H27N2O4F 0.78 463.4 yl-propionyl)-1,2,3,4-tetrahydro- 462.20 LC-MS 1FA isoquinolin-8-yl]-phenyl}-acetic acid 350 (±)-{4-Ethoxy-3-[5-fluoro-2-(2- C30H31N2O4F 0.77 503.4 5,6,7,8-tetrahydro-quinolin-8-yl- 502.23 LC-MS 1FA acetyl)-1,2,3,4-tetrahydro- isoquinolin-8-yl]-phenyl}-acetic acid 351 (±)-{4-Ethoxy-3-[5-fluoro-2-(2- C28H29N2O4F 0.82 477.4 methyl-3-pyridin-2-yl-propionyl)- 476.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 352 (±)-{3-Ethoxy-4-[5-fluoro-2-(2- C28H29N2O4F 0.82 477.4 methyl-3-pyridin-2-yl-propionyl)- 476.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid

Method C: A solution of (±)-chroman-4-yl-acetic acid (7.5 mg, 39 μmol, 1.0 eq.) and [4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-3-isopropoxy-phenyl]-acetic acid tert-butyl ester (16 mg, 39 μmol, 1.0 eq.) in MeCN (0.5 mL) was treated with 4-(dimethylamino)pyridine (7.2 mg, 59 μmol, 1.5 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (11.3 mg, 59 μmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 18 hours. The crude mixture was concentrated in vacuo. To an ice-cooled solution of the residue in DCM (0.1 mL), TFA (0.13 mL) was added slowly. The mixture was stirred at r.t. for 2 hours. The mixture was concentrated in vacuo without heating. The residue was redissolved in MeCN (1 mL) and purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white foam.

Listed in Table 22 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 22 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 353 (±)-{4-[2-(2-Chroman-4-yl-acetyl)- C31H32NO5F 1.19 518.4 5-fluoro-1,2,3,4-tetrahydro- 517.23 LC-MS 1FA isoquinolin-8-yl]-3-isopropoxy- phenyl}-acetic acid 354 {4-[5-Fluoro-2-(3-methyl-3-phenyl- C31H34NO4F 1.25 504.4 butyryl)-1,2,3,4-tetrahydro- 503.25 LC-MS 1FA isoquinolin-8-yl]-3-isopropoxy- phenyl}-acetic acid 355 {4-[5-Fluoro-2-((S)-3-phenyl- C30H32NO4F 1.21 490.4 butyryl)-1,2,3,4-tetrahydro- 489.23 LC-MS 1FA isoquinolin-8-yl]-3-isopropoxy- phenyl}-acetic acid 356 {4-[5-Fluoro-2-((R)-3-phenyl- C30H32NO4F 1.21 490.4 butyryl)-1,2,3,4-tetrahydro- 489.23 LC-MS 1FA isoquinolin-8-yl]-3-isopropoxy- phenyl}-acetic acid 357 {4-[5-Fluoro-2-((1R,2R)-2-phenyl- C30H30NO4F 1.21 488.4 cyclopropanecarbonyl)-1,2,3,4- 487.22 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-3- isopropoxy-phenyl}-acetic acid

Method D: To a solution of 3-(4-fluoro-phenyl)-3-methyl-butyric acid (22 mg, 0.11 mmol, 1.1 eq.) in DCM (2 mL), DIPEA (70 μL, 0.41 mmol, 4 eq.) and TBTU (36 mg, 0.11 mmol, 1.1 eq.) were added in sequence. The resulting solutions were stirred at room temperature for 30 minutes. Then [4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-3-methoxy-phenyl]-acetic acid ethyl ester (35 mg, 0.10 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in DMF (0.8 mL). 1M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 3 hours. The solution was carefully neutralized with formic acid (0.5 mL), purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 23 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding acid as starting materials.

TABLE 23 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 358 (4-{5-Fluoro-2-[3-(4-fluoro-phenyl)- C29H29NO4F2 1.16 494.4 3-methyl-butyryl]-1,2,3,4-tetrahydro- 493.21 LC-MS 1FA isoquinolin-8-yl}-3-methoxy-phenyl)- acetic acid 359 (±)-{4-[2-(2-Chroman-4-yl-acetyl)-5- C29H28NO5F 1.09 490.4 fluoro-1,2,3,4-tetrahydro- 489.20 LC-MS 1FA isoquinolin-8-yl]-3-methoxy-phenyl}- acetic acid 360 (±)-{4-[5-Fluoro-2-(2-indan-1-yl- C29H28NO4F 1.15 474.4 acetyl)-1,2,3,4-tetrahydro- 473.20 LC-MS 1FA isoquinolin-8-yl]-3-methoxy-phenyl}- acetic acid 361 (±)-{3-[5-Fluoro-2-(trans-2-pyridin-2- C27H25N2O4F 0.87 461.4 yl-cyclopropanecarbonyl)-1,2,3,4- 460.18 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- methoxy-phenyl}-acetic acid 362 (±)-{3-[2-(2-1,3-Dihydro- C28H26NO5F 1.02 476.4 isobenzofuran-1-yl-acetyl)-5-fluoro- 475.18 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8-yl]- 4-methoxy-phenyl}-acetic acid

Example 363 (3-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid (C29H29NO4F2, MW=493.21)

To a solution of 3-(4-fluoro-phenyl)-3-methyl-butyric acid (20 mg, 0.1 mmol, 1.0 eq.) in DCM (1 mL), 1-hydroxybenzotriazole hydrate (HOBt) (14 mg, 0.1 mmol, 1.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol, 1.0 eq.) were added in sequence. The resulting solution was stirred at r.t. for 2 minutes. Then a solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (34 mg, 0.1 mmol, 1.0 eq.) and triethylamine (42 μL, 0.3 mmol, 3.0 eq.) in DCM (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in DMF (0.8 mL). 1M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 3 hours. The solution was carefully neutralized with formic acid (0.5 mL), and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a white solid.

LC-MS 3: t_(R)=0.92 min; [M+H]⁺=494.3

Carbamate Formation and Concomitant Saponification

To a solution of 8-(2-ethoxy-5-ethoxycarbonylmethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-nitro-phenyl ester (40 mg, 0.08 mmol, 1 eq.) and (R)-(+)-sec-phenethyl alcohol (28 mg. 0.23 mmol, 3 eq.) in THF (2 mL), potasssium tert-butoxide (27 mg, 0.23 mmol, 3 eq.) was added. The mixture was stirred at r.t. for 3 hours. The reaction mixture was quenched with formic acid (6 eq.) and the flask was opened and let stand at r.t. to allow solvent evaporation (2 days). The residue was dissolved in MeCN/H₂O 1:1 (1 mL) and DMF (0.2 mL). The resulting solution was purified by prep. HPLC (column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 24 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding nitrophenyl carbamate 5 and the corresponding alcohol as starting materials.

TABLE 24 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 364 8-(5-Carboxymethyl-2-ethoxy- C28H28NO5F 1.23 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid (R)-1- phenyl-ethyl ester 365 8-(5-Carboxymethyl-2-ethoxy- C25H24N3O5F 1.00 466.4 phenyl)-5-fluoro-3,4-dihydro-1H- 465.17 LC-MS 1FA isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 366 8-(5-Carboxymethyl-2-ethoxy- C27H26N2O5F2 1.12 497.3 phenyl)-5-fluoro-3,4-dihydro-1H- 496.18 LC-MS 1FA isoquinoline-2-carboxylic acid 3- fluoro-5-methyl-pyridin-2-ylmethyl ester 367 8-(5-Carboxymethyl-2-ethoxy- C25H26N3O5F 1.01 468.4 phenyl)-5-fluoro-3,4-dihydro-1H- 467.19 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-2H-pyrazol-3-ylmethyl ester 368 8-(5-Carboxymethyl-2-ethoxy- C28H28NO5F 1.23 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid (S)-1- phenyl-ethyl ester 369 8-(5-Carboxymethyl-2-ethoxy- C26H30NO5F 1.26 456.4 phenyl)-5-fluoro-3,4-dihydro-1H- 455.21 LC-MS 1FA isoquinoline-2-carboxylic acid cyclopentylmethyl ester 370 8-(5-Carboxymethyl-2-ethoxy- C25H30NO5F 1.25 444.4 phenyl)-5-fluoro-3,4-dihydro-1H- 443.21 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methyl-butyl ester 371 8-(5-Carboxymethyl-2-ethoxy- C27H27N2O5F 0.97 479.4 phenyl)-5-fluoro-3,4-dihydro-1H- 478.19 LC-MS 1FA isoquinoline-2-carboxylic acid 6- methyl-pyridin-2-ylmethyl ester 372 8-(5-Carboxymethyl-2-ethoxy- C24H26NO5F 1.15 428.4 phenyl)-5-fluoro-3,4-dihydro-1H- 427.18 LC-MS 1FA isoquinoline-2-carboxylic acid cyclopropylmethyl ester 373 8-(5-Carboxymethyl-2-ethoxy- C28H28NO5F 1.21 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid phenethyl ester 374 8-(5-Carboxymethyl-2-ethoxy- C29H30NO5F 1.25 492.4 phenyl)-5-fluoro-3,4-dihydro-1H- 491.21 LC-MS 1FA isoquinoline-2-carboxylic acid (R)-2- phenyl-propyl ester 375 8-(5-Carboxymethyl-2-ethoxy- C25H28NO5F 1.21 442.4 phenyl)-5-fluoro-3,4-dihydro-1H- 441.20 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methyl-but-2-enyl ester 376 8-(5-Carboxymethyl-2-ethoxy- C24H28NO5F 1.20 430.4 phenyl)-5-fluoro-3,4-dihydro-1H- 429.20 LC-MS 1FA isoquinoline-2-carboxylic acid butyl ester 377 8-(5-Carboxymethyl-2-ethoxy- C24H28NO5F 1.20 430.4 phenyl)-5-fluoro-3,4-dihydro-1H- 429.20 LC-MS 1FA isoquinoline-2-carboxylic acid isobutyl ester 378 8-(5-Carboxymethyl-2-ethoxy- C23H26NO6F 1.03 432.4 phenyl)-5-fluoro-3,4-dihydro-1H- 431.17 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methoxy-ethyl ester 379 8-(5-Carboxymethyl-2-ethoxy- C25H28NO5F 1.20 442.4 phenyl)-5-fluoro-3,4-dihydro-1H- 441.20 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methyl-but-3-enyl ester 380 (±)-8-(5-Carboxymethyl-2-ethoxy- C25H30NO5F 1.25 444.4 phenyl)-5-fluoro-3,4-dihydro-1H- 443.20 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-butyl ester 381 8-(5-Carboxymethyl-2-ethoxy- C24H24NO5F 1.09 426.4 phenyl)-5-fluoro-3,4-dihydro-1H- 425.16 LC-MS 1FA isoquinoline-2-carboxylic acid but-3- ynyl ester 382 8-(5-Carboxymethyl-2-ethoxy- C25H30NO6F 1.02 460.4 phenyl)-5-fluoro-3,4-dihydro-1H- 459.21 LC-MS 1FA isoquinoline-2-carboxylic acid 3- hydroxy-3-methyl-butyl ester 383 8-(5-Carboxymethyl-2-ethoxy- C26H32NO6F 1.14 474.4 phenyl)-5-fluoro-3,4-dihydro-1H- 473.22 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methoxy-3-methyl-butyl ester 384 (±)-8-(5-Carboxymethyl-2-ethoxy- C25H28NO6F 1.06 458.4 phenyl)-5-fluoro-3,4-dihydro-1H- 457.19 LC-MS 1FA isoquinoline-2-carboxylic acid tetrahydro-furan-2-ylmethyl ester 385 8-(4-Carboxymethyl-2-ethoxy- C28H28NO5F 1.24 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid (R)-1- phenyl-ethyl ester 386 8-(4-Carboxymethyl-2-ethoxy- C25H24N3O5F 1.01 466.4 phenyl)-5-fluoro-3,4-dihydro-1H- 465.17 LC-MS 1FA isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 387 8-(4-Carboxymethyl-2-ethoxy- C27H26N2O5F2 1.12 497.4 phenyl)-5-fluoro-3,4-dihydro-1H- 496.18 LC-MS 1FA isoquinoline-2-carboxylic acid 3- fluoro-5-methyl-pyridin-2-ylmethyl ester 388 8-(4-Carboxymethyl-2-ethoxy- C25H26N3O5F 1.03 468.4 phenyl)-5-fluoro-3,4-dihydro-1H- 467.19 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-2H-pyrazol-3-ylmethyl ester 389 8-(4-Carboxymethyl-2-ethoxy- C28H28NO5F 1.24 478.3 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 1FA isoquinoline-2-carboxylic acid (S)-1- phenyl-ethyl ester 390 8-(4-Carboxymethyl-2-ethoxy- C27H27N2O5F 0.98 479.4 phenyl)-5-fluoro-3,4-dihydro-1H- 478.19 LC-MS 1FA isoquinoline-2-carboxylic acid 6- methyl-pyridin-2-ylmethyl ester 391 8-(4-Carboxymethyl-2-ethoxy- C24H26NO5F 1.16 428.4 phenyl)-5-fluoro-3,4-dihydro-1H- 427.18 LC-MS 1FA isoquinoline-2-carboxylic acid cyclopropylmethyl ester 392 8-(4-Carboxymethyl-2-ethoxy- C26H30NO5F 1.28 456.3 phenyl)-5-fluoro-3,4-dihydro-1H- 455.21 LC-MS 1FA isoquinoline-2-carboxylic acid cyclopentylmethyl ester 393 8-(4-Carboxymethyl-2-ethoxy- C25H30NO5F 1.26 444.4 phenyl)-5-fluoro-3,4-dihydro-1H- 443.21 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methyl-butyl ester 394 8-(5-Carboxymethyl-2-ethoxy- C26H25N2O5F 1.01 465.4 phenyl)-5-fluoro-3,4-dihydro-1H- 464.18 LC-MS 1FA isoquinoline-2-carboxylic acid pyridin- 2-ylmethyl ester 395 8-(4-Carboxymethyl-2-ethoxy- C26H25N2O5F 1.01 465.4 phenyl)-5-fluoro-3,4-dihydro-1H- 464.18 LC-MS 1FA isoquinoline-2-carboxylic acid pyridin- 2-ylmethyl ester 396 8-(5-Carboxymethyl-2-ethoxy- C27H32NO5F 1.31 470.4 phenyl)-5-fluoro-3,4-dihydro-1H- 469.23 LC-MS 1FA isoquinoline-2-carboxylic acid cyclohexylmethyl ester 397 8-(4-Carboxymethyl-2-ethoxy- C27H32NO5F 1.32 470.4 phenyl)-5-fluoro-3,4-dihydro-1H- 469.23 LC-MS 1FA isoquinoline-2-carboxylic acid cyclohexylmethyl ester

Carbamate Formation and Subsequent Saponification

Method A: To a solution of [4-ethoxy-3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (72 mg, 0.20 mmol, 1.0 eq.) and DIPEA (46 μL, 0.50 mmol, 2.5 eq.) in DCM (3 mL), carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-fluoro-benzyl ester (65 mg, 0.24 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 1 hour. The reaction was quenched with 1M aq. citric acid soln. (3 mL). The layers were separated over phase separators. The aq. phase was extracted with DCM (3×). The comb. org. phases were concentrated in vacuo. To a solution of the residue in DMF (0.9 mL), 2M aq. NaOH (0.5 mL) was added. The solution was stirred at r.t. for 2 hours. Formic acid (0.2 mL) was added. The resulting solution was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white foam.

Listed in Table 25 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding carbonate 3 as starting materials.

TABLE 25 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 398 8-(5-Carboxymethyl-2-ethoxy- C27H25NO5F2 1.20 482.4 phenyl)-5-fluoro-3,4-dihydro-1H- 481.17 LC-MS 1FA isoquinoline-2-carboxylic acid 4- fluoro-benzyl ester 399 8-(5-Carboxymethyl-2-ethoxy- C27H25NO5F2 1.20 482.4 phenyl)-5-fluoro-3,4-dihydro-1H- 481.17 LC-MS 1FA isoquinoline-2-carboxylic acid 3- fluoro-benzyl ester 400 8-(5-Carboxymethyl-2-ethoxy- C27H25NO5F2 1.19 482.3 phenyl)-5-fluoro-3,4-dihydro-1H- 481.17 LC-MS 1FA isoquinoline-2-carboxylic acid 2- fluoro-benzyl ester 401 8-(5-Carboxymethyl-2-ethoxy- C27H24NO5F3 1.21 500.3 phenyl)-5-fluoro-3,4-dihydro-1H- 499.16 LC-MS 1FA isoquinoline-2-carboxylic acid 2,5- difluoro-benzyl ester 402 8-(5-Carboxymethyl-2-ethoxy- C27H24NO5ClF2 1.25 516.3 phenyl)-5-fluoro-3,4-dihydro-1H- 515.13 LC-MS 1FA isoquinoline-2-carboxylic acid 5- chloro-2-fluoro-benzyl ester 403 8-(5-Carboxymethyl-2-ethoxy- C27H24NO5F3 1.21 500.3 phenyl)-5-fluoro-3,4-dihydro-1H- 499.16 LC-MS 1FA isoquinoline-2-carboxylic acid 2,4- difluoro-benzyl ester 404 8-(4-Carboxymethyl-2-ethoxy- C27H25NO5F2 1.21 482.4 phenyl)-5-fluoro-3,4-dihydro-1H- 481.17 LC-MS 1FA isoquinoline-2-carboxylic acid 4- fluoro-benzyl ester 405 8-(4-Carboxymethyl-2-ethoxy- C27H25NO5F2 1.21 482.4 phenyl)-5-fluoro-3,4-dihydro-1H- 481.17 LC-MS 1FA isoquinoline-2-carboxylic acid 3- fluoro-benzyl ester 406 8-(4-Carboxymethyl-2-ethoxy- C27H25NO5F2 1.21 482.4 phenyl)-5-fluoro-3,4-dihydro-1H- 481.17 LC-MS 1FA isoquinoline-2-carboxylic acid 2- fluoro-benzyl ester 407 8-(4-Carboxymethyl-2-ethoxy- C27H24NO5F3 1.22 500.3 phenyl)-5-fluoro-3,4-dihydro-1H- 499.16 LC-MS 1FA isoquinoline-2-carboxylic acid 2,5- difluoro-benzyl ester 408 8-(4-Carboxymethyl-2-ethoxy- C27H24NO5ClF2 1.27 516.3 phenyl)-5-fluoro-3,4-dihydro-1H- 515.13 LC-MS 1FA isoquinoline-2-carboxylic acid 5- chloro-2-fluoro-benzyl ester 409 8-(4-Carboxymethyl-2-ethoxy- C27H24NO5F3 1.22 500.3 phenyl)-5-fluoro-3,4-dihydro-1H- 499.16 LC-MS 1FA isoquinoline-2-carboxylic acid 2,4- difluoro-benzyl ester

Method B: To an ice-cooled solution of [3-ethoxy-4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (112 mg, 0.3 mmol, 1.0 eq.) and DIPEA (0.15 mL, 0.9 mmol, 3.0 eq.) in DMF (3.6 mL), benzyl chloroformate (50 μL, 0.33 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 48 hours. Formic acid was added (0.2 mL). The resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. To a solution of the previous ester in DMF (3.6 mL), 2M aq. NaOH soln. (1.8 mL) was added. The solution was stirred at r.t. for 1 hour. Formic acid was added (0.2 mL). The resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired acid as a white foam.

Listed in Table 26 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 as starting material.

TABLE 26 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 410 8-(4-Carboxymethyl-2-ethoxy- C27H26NO5F 1.20 464.4 phenyl)-5-fluoro-3,4-dihydro-1H- 463.18 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 411 8-[4-Carboxymethyl-2-(2,2,2- C27H23NO5F4 1.22 518.3 trifluoro-ethoxy)-phenyl]-5-fluoro- 517.15 LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester

Suzuki Cross-Coupling and Subsequent Saponification

Method A: To a mixture under N₂ of (3-bromo-4-difluoromethoxy-phenyl)-acetic acid ethyl ester (32 mg, 0.10 mmol, 1.00 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (49 mg, 0.10 mmol, 1.00 eq.) and sodium carbonate (42 mg, 0.40 mmol, 4.00 eq) in toluene/MeOH/water 20:4:1 (2.0 mL), tetrakis(triphenylphosphine) palladium (0) (5.8 mg, 5 μmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered over celite, and concentrated in vacuo. The residue, redissolved in DMF (1 mL) and formic acid (0.2 mL) was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. The resulting ester was redissolved in DMF (0.5 mL) and 2M aq. NaOH soln. (0.2 mL) was added. The mixture was stirred at r.t. for 1 hour. Formic acid (0.2 mL) was added and the resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white foam.

Listed in Table 27 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding halogenated compound 9 as starting material.

TABLE 27 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 412 8-(5-Carboxymethyl-2- C26H22NO5F3 1.16 486.3 difluoromethoxy-phenyl)-5-fluoro- 485.15 LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 413 8-[5-Carboxymethyl-2-(2,2- C27H24NO5F3 1.15 500.3 difluoro-ethoxy)-phenyl]-5-fluoro- 499.16 LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 414 (±)-8-[5-(1-Carboxy-ethoxy)-2- C27H26NO6F 1.17 480.3 methoxy-phenyl]-5-fluoro-3,4- 479.17 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 415 (±)-8-[5-(1-Carboxy-propoxy)-2- C28H28NO6F 1.22 494.4 methoxy-phenyl]-5-fluoro-3,4- 493.19 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 416 8-(2-Carboxymethyl-5-chloro- C25H21NO4ClF 1.23 454.3 phenyl)-5-fluoro-3,4-dihydro-1H- 453.11 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester

Method B: A mixture under N₂ of palladium (II) acetate (0.4 mg, 2 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.7 mg, 4 μmol, 0.02 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (82.3 mg, 0.2 mmol, 1.00 eq.) and potassium phosphate (84.9 mg, 0.4 mmol, 2.00 eq.) in toluene (0.6 mL) and water (35 was stirred at r.t. during 2 min. A solution of (2-bromo-3-methoxy-phenoxy)-acetic acid ethyl ester (64 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue, redissolved in MeCN/H₂O (1.8 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. The residue was redissolved in DMF (1.0 mL) and 2M aq. NaOH soln. (0.4 mL) was added. The resulting mixture was stirred at r.t. for 60 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white foam.

Listed in Table 28 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding halogenated compound 9 as starting material.

TABLE 28 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 417 8-(2-Carboxymethoxy-6-methoxy- C26H24NO6F 1.11 466.4 phenyl)-5-fluoro-3,4-dihydro-1H- 465.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 418 8-(2-Carboxymethyl-6-methoxy- C26H24NO5F 1.11 450.4 phenyl)-5-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 419 8-(2-tert-Butoxy-5-carboxymethyl- C29H30NO5F 1.29 492.4 phenyl)-5-fluoro-3,4-dihydro-1H- 491.21 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 420 8-(5-Carboxymethyl-2- C27H27N2O4F 1.11 463.4 dimethylamino-phenyl)-5-fluoro- 462.20 LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 421 8-[5-Carboxymethyl-2-(2,2,2- C27H23NO5F4 1.20 518.3 trifluoro-ethoxy)-phenyl]-5-fluoro- 517.15 LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 422 8-[5-Carboxymethyl-2-(2-fluoro- C27H25NO5F2 1.12 482.3 ethoxy)-phenyl]-5-fluoro-3,4- 481.17 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 423 8-(3-Carboxymethyl-2-methoxy- C26H24NO5F 1.17 450.4 phenyl)-5-fluoro-3,4-dihydro-1H- 449.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 424 8-(4-Carboxymethoxy-2-methoxy- C26H24NO6F 1.15 466.3 phenyl)-5-fluoro-3,4-dihydro-1H- 465.16 LC-MS 1FA isoquinoline-2-carboxylic acid benzyl ester 425 (±)-8-[4-(1-Carboxy-ethyl)-2- C28H28NO5F 1.24 478.4 ethoxy-phenyl]-5-fluoro-3,4- 477.20 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester

Method C: A mixture under N₂ of palladium (II) acetate (0.44 mg, 2 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.64 mg, 4 μmol, 0.02 eq.), [5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-((1R,2R)-2-5 phenyl-cyclopropyl)-methanone (95.4 mg, 0.2 mmol, 1.00 eq.) and potassium phosphate (85 mg, 0.4 mmol, 2.00 eq.) in toluene (0.6 mL) and water was stirred at r.t. for 2 min. A solution of [3-bromo-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (68.2 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 48 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The crude residue, redissolved in MeCN (1.3 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. To a solution of the previous ester in DMF (1 mL), 2M aq. NaOH soln. (0.4 mL) was added. The resulting solution was stirred at r.t. for 18 hours.

Formic acid (0.2 mL) was added. The mixture was purified by prep. HPLC (column: Waters XBridge, 19×30 mm, 5 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a colorless oil.

Listed in Table 29 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding halogenated compound 9 as starting material.

TABLE 29 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 426 [3-[5-Fluoro-2-((1R,2R)-2-phenyl- C29H25NO4F4 1.18 528.3 cyclopropanecarbonyl)-1,2,3,4- 527.17 LC-MS 1FA tetrahydro-isoquinolin-8-yl]-4- (2,2,2-trifluoro-ethoxy)-phenyl]- acetic acid 427 {4-(2-Fluoro-ethoxy)-3-[5-fluoro-2- C29H27NO4F2 1.10 492.4 ((1R,2R)-2-phenyl- 491.19 LC-MS 1FA cyclopropanecarbonyl)-1,2,3,4- tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 428 {4-tert-Butoxy-3-[5-fluoro-2- C31H32NO4F 1.25 502.4 ((1R,2R)-2-phenyl- 501.23 LC-MS 1FA cyclopropanecarbonyl)-1,2,3,4- tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 429 1-{3-[5-Fluoro-2-((1R,2R)-2- C30H28NO4F 1.17 486.4 phenyl-cyclopropanecarbonyl)- 485.20 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-4-methoxy-phenyl}- cyclopropanecarboxylic acid

Example 430 8-(5-Carboxymethyl-2-cyclopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C28H26NO5F, MW=475.18)

A mixture under N₂ of palladium (II) acetate (0.4 mg, 2 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.7 mg, 4 μmol, 0.02 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (82.3 mg, 0.2 mmol, 1.00 eq.) and potassium phosphate (84.9 mg, 0.4 mmol, 2.00 eq.) in toluene (0.6 mL) and water (35 μL) was stirred at r.t. during 2 min. A solution of (3-chloro-4-cyclopropoxy-phenyl)-acetic acid tert-butyl ester (57 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue, redissolved in MeCN (1.8 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. Trifluoroacetic acid (0.23 mL) was slowly added to an ice-cooled solution of the previous tert-butyl ester in DCM (0.23 mL). The reaction mixture was stirred at r.t. for 1.5 hours. The mixture was concentrated in vacuo without heating and the residue was redissolved in DMF (1.3 mL). Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a white foam.

LC-MS 1FA: t_(R)=1.20 min; [M+H]⁺=476.4

Example 431 8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C29H28N205, MW=484.20)

A mixture under N₂ of palladium(II) acetate (0.21 mg, 0.9 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.78 mg, 1.9 mmol, 0.02 eq.), [4-isopropoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (34 mg, 94.3 μmol, 1.00 eq.) and potassium phosphate (40 mg, 0.19 mmol, 2.00 eq.) in toluene (0.3 mL) and water (0.04 mL) was stirred at r.t. for 2 min. A solution of 8-chloro-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (32.1 mg, 94.3 μmol, 1.00 eq.) in toluene (0.3 mL) was added and the mixture was stirred at 100° C. for 48 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue, redissolved in MeCN/H₂O (1.6 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. The residue was redissolved in DMF (0.45 mL) and 2M aq. NaOH soln. (0.2 mL) was added. The resulting mixture was stirred at r.t. for 1 hour. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a milky oil.

LC-MS 1FA: t_(R)=1.17 min; [M+H]⁺=485.4

Urea Formation and Subsequent Saponification

Method A: To a solution of [4-ethoxy-3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (40 mg, 0.11 mmol, 1.00 eq.) and NEt₃ (47 μL, 0.34 mmol, 3.00 eq.) in MeCN (1 mL), 2-fluorobenzyl isocyanate (18 mg, 0.12 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture was stirred at r.t. for 18 hours. 2M aq. NaOH soln. (0.50 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 30 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 and the corresponding isocyanate as starting materials.

TABLE 30 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 432 {4-Ethoxy-3-[5-fluoro-2-(2-fluoro- C27H26N2O4F2 1.08 481.3 benzylcarbamoyl)-1,2,3,4- 480.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 433 {4-Ethoxy-3-[5-fluoro-2-(3-fluoro- C27H26N2O4F2 1.08 481.3 benzylcarbamoyl)-1,2,3,4- 480.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 434 {4-Ethoxy-3-[5-fluoro-2-(4-fluoro- C27H26N2O4F2 1.08 481.3 benzylcarbamoyl)-1,2,3,4- 480.19 LC-MS 1TFA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 435 [4-Ethoxy-3-(5-fluoro-2- C28H29N2O4F 1.10 477.4 phenethylcarbamoyl-1,2,3,4- 476.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl)- phenyl]-acetic acid 436 {3-[2-(2-Chloro-benzylcarbamoyl)- C27H26N2O4ClF 1.12 497.3 5-fluoro-1,2,3,4-tetrahydro- 496.16 LC-MS 1FA isoquinolin-8-yl]-4-ethoxy-phenyl}- acetic acid 437 {4-Ethoxy-3-[5-fluoro-2-(2- C28H29N2O5F 1.08 493.3 methoxy-benzylcarbamoyl)- 492.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-phenyl}-acetic acid 438 [3-(2-Benzylcarbamoyl-5-fluoro- C27H27N2O4F 1.07 463.3 1,2,3,4-tetrahydro-isoquinolin-8- 462.20 LC-MS 1TFA yl)-4-ethoxy-phenyl]-acetic acid 439 [4-Ethoxy-3-(5-fluoro-2- C23H27N2O4F 1.00 415.4 propylcarbamoyl-1,2,3,4- 414.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl)- phenyl]-acetic acid 440 {3-Ethoxy-4-[5-fluoro-2-(2-fluoro- C27H26N2O4F2 1.08 481.3 benzylcarbamoyl)-1,2,3,4- 480.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 441 {3-Ethoxy-4-[5-fluoro-2-(3-fluoro- C27H26N2O4F2 1.08 481.3 benzylcarbamoyl)-1,2,3,4- 480.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 442 {3-Ethoxy-4-[5-fluoro-2-(4-fluoro- C27H26N2O4F2 1.08 481.4 benzylcarbamoyl)-1,2,3,4- 480.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 443 [3-Ethoxy-4-(5-fluoro-2- C28H29N2O4F 1.10 477.4 phenethylcarbamoyl-1,2,3,4- 476.21 LC-MS 1FA tetrahydro-isoquinolin-8-yl)- phenyl]-acetic acid 444 {4-[2-(2-Chloro-benzylcarbamoyl)- C27H26N2O4ClF 1.12 497.3 5-fluoro-1,2,3,4-tetrahydro- 496.16 LC-MS 1FA isoquinolin-8-yl]-3-ethoxy-phenyl}- acetic acid 445 {3-Ethoxy-4-[5-fluoro-2-(2- C28H29N2O5F 1.09 493.3 methoxy-benzylcarbamoyl)- 492.21 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-8- yl]-phenyl}-acetic acid 446 [4-(2-Benzylcarbamoyl-5-fluoro- C27H27N2O4F 1.07 463.4 1,2,3,4-tetrahydro-isoquinolin-8- 462.20 LC-MS 1FA yl)-3-ethoxy-phenyl]-acetic acid 447 [3-Ethoxy-4-(5-fluoro-2- C23H27N2O4F 1.01 415.4 propylcarbamoyl-1,2,3,4- 414.20 LC-MS 1FA tetrahydro-isoquinolin-8-yl)- phenyl]-acetic acid

Method B: 2-(Aminomethyl)pyridine (15 μL, 0.14 mmol, 1.00 eq.) was dissolved in MeCN (1 mL). N-Ethyldiisopropylamine (72 μL, 0.42 mmol, 3.00 eq.) was added followed by 1,1′-carbonyldiimidazole (24 mg, 0.15 mmol, 1.05 eq.). The resulting mixture was stirred at 45° C. for 3 hours. [3-Ethoxy-4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (50 mg, 0.14 mmol, 1.00 eq.) was added and the mixture was heated to 70° C. for 18 hours. The reaction mixture was partially purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, basic conditions) and concentrated in vacuo. To a solution of the residue in DMF (0.50 mL), 2M aq. NaOH soln. (0.50 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1.00 mL), filtered and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 31 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 2 as starting material.

TABLE 31 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 448 (3-Ethoxy-4-{5-fluoro-2-[(pyridin-2- C26H26N3O4F 0.80 464.4 ylmethyl)-carbamoyl]-1,2,3,4- 463.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 449 (4-Ethoxy-3-{5-fluoro-2-[(pyridin-2- C26H26N3O4F 0.80 464.4 ylmethyl)-carbamoyl]-1,2,3,4- 463.19 LC-MS 1FA tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid

Synthesis of Precursors and Intermediates

General Method for the Synthesis of the Nitrostyrenes 19

5-Chloro-2-(trifluoromethyl)benzaldehyde (10.75 g, 50.0 mmol, 1.00 eq.) was dissolved in nitromethane (30 mL). Molecular sieves (4 A 961 mg), butylamine (0.59 mL, 5.9 mmol, 0.12 eq.) and acetic acid (0.58 mL, 10.2 mmol, 0.20 eq.) were added and the mixture was stirred at 95° C. for 1 hour. The mixture was transferred into a new flask to remove the mol. sieves. The solvent was removed in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 40 mL/min, 30 fractions of 40 mL, Heptane to Heptane+12% AcOEt) to yield the desired nitrostyrene as a brown oil.

Listed in Table 32 below are nitrostyrenes 19, prepared according to the above-mentioned method, with corresponding benzaldehyde 20, 22, or 26 as starting material.

TABLE 32 t_(R) [min] Formula LC-MS Nitrostyrenes 19 MW Method MS-data m/z [M + H]⁺ 4-Chloro-2-((E)-2-nitro-vinyl)-1- C9H5NO2ClF3 0.94 no ionization trifluoromethyl-benzene 251.00 LC-MS 3 4-Bromo-1-fluoro-2-((E)-2-nitro-vinyl)- C8H5NO2BrF 0.89 no ionization benzene 244.95 LC-MS 3 4-Bromo-1-chloro-2-((E)-2-nitro-vinyl)- C8H5NO2BrCl 0.94 no ionization benzene 260.92 LC-MS 3 4-Bromo-1-methyl-2-((E)-2-nitro-vinyl)- C9H8NO2Br 0.92 no ionization benzene 240.97 LC-MS 3 1-Bromo-4-chloro-2-((E)-2-nitro-vinyl)- C8H5NO2BrCl 0.93 no ionization benzene 260.92 LC-MS 3 1-Bromo-4-methoxy-2-((E)-2-nitro- C9H8NO3Br 0.92 no ionization vinyl)-benzene 260.92 LC-MS 3 1-Bromo-4-fluoro-2-((E)-2-nitro-vinyl)- C8H5NO2BrF 0.89 no ionization benzene 244.95 LC-MS 3 1-Fluoro-4-methoxy-2-((E)-2-nitro-vinyl)- C9H8NO3F 0.86 no ionization benzene 197.05 LC-MS 3

General Method for the Preparation of the Phenethylamines (or the Corresponding Hydrochloride Salt) 18

Sulfuric acid (1.78 mL) was added dropwise to a stirred suspension of LiAlH₄ (2.66 g, 66.55 mmol, 4.46 eq.) in THF (100 mL) under ice-cooling. After stirring for 20 min, a solution of 4-chloro-2-((E)-2-nitro-vinyl)-1-trifluoromethyl-benzene (4.02 g, 14.91 mmol, 1.00 eq.) in THF (10.5 mL) was added dropwise within 20 min under ice-cooling. After 10 min, the cooling bath was removed and the mixture was warmed up gently by using a heat gun until the mixture gently boiled. After 5 min the mixture was again cooled to 0° C. and carefully hydrolyzed by the dropwise addition of iPrOH (11 mL) and then 2M aq. NaOH soln. (8.2 mL). The resulting suspension was filtered off and the filter cake was rinsed with THF. The fitrate was concentrated in vacuo to give the desired phenethylamine.

The free amine was dissolved in Et₂O (54 mL) and iPrOH (2.1 mL) and acidified with 2M HCl in Et₂O soln. (29 mL). The suspension was filtered off and the filter cake was rinsed with Et₂O. The resulting white solid was dried under h.v. The HCl salt was used without further purification.

Listed in Table 33 below are phenethylamines 18 or phenethylamine hydrochlorides 18, prepared according to the above-mentioned method, with corresponding nitrostyrenes 19 as starting material.

TABLE 33 t_(R) [min] Formula LC-MS Intermediates 18 MW Method MS-data m/z [M + H]⁺ 2-(5-Chloro-2-trifluoromethyl-phenyl)- C9H9NClF3 0.59 no ionization ethylamine hydrochloride 223.04 LC-MS 3 2-(5-Bromo-2-fluoro-phenyl)-ethylamine C8H9NBrF 0.50 218.2 hydrochloride 216.99 LC-MS 3 2-(5-Bromo-2-chloro-phenyl)-ethylamine C8H9NBrCl 0.55 234.2 hydrochloride 232.96 LC-MS 3 2-(5-Bromo-2-methyl-phenyl)- C9H12NBr 0.56 no ionization ethylamine hydrochloride 213.02 LC-MS 3 2-(2-Bromo-5-chloro-phenyl)-ethylamine C8H9NBrCl 0.55 234.1 hydrochloride 232.96 LC-MS 3 2-(2-Bromo-5-methoxy-phenyl)- C9H12NOBr 0.53 230.3 ethylamine hydrochloride 229.01 LC-MS 3 2-(2-Bromo-5-fluoro-phenyl)-ethylamine C8H9NBrF 0.50 218.2 hydrochloride 216.99 LC-MS 3 2-(2-Fluoro-5-methoxy-phenyl)- C9H12NOF 0.45 170.2 ethylamine 169.09 LC-MS 3

General Method for the Synthesis of the 3,4-Dihydroisoquinolines 16

A mixture of 2-(5-bromo-2-fluoro-phenyl)-ethylamine hydrochloride (7.65 g, 27.2 mmol, 1.0 eq.), and ethyl formiate (2.91 mL, 36.2 mmol, 1.1 eq.) was stirred at 70° C. for 6 hours. The reaction mixture was allowed to cool to r.t. and partitioned between AcOEt (150 mL) and water (150 mL). The layers were separated. The org. phase was washed with water (1×150 mL), sat. aq. NaCl soln. (1×150 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give the corresponding formamide.

The formamide was dissolved in DCM (272 mL). Oxalyl chloride (2.59 mL, 30.0 mmol, 1.1 eq.) was added. The mixture was stirred at r.t. for 30 min, then cooled to −10° C. Iron-(III)-chlorid anhydrous (5.3 g, 32.7 mmol, 1.2 eq.) was added to the cold mixture. The resulting mixture was allowed to slowly warm to r.t. and stirred at r.t. for 4 hours. The reaction was quenched with 2M aq. HCl soln. (272 mL) and the biphasic system was stirred at r.t. for 1 hour. The layers were separated. The aq. phase was extracted with DCM (1×150 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×150 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give the oxazolo intermediate.

The oxazolo intermediate was dissolved in MeOH (310 mL) and conc. H₂SO₄ (16.4 mL). The resulting mixture was refluxed for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between water (150 mL) and AcOEt (150 mL). The layers were separated. The org. phase was extracted with 2M aq. HCl soln. (2×70 mL). The comb. 3 acidic aq. phases were basified with 25% NH₃ and extracted with DCM (3×150 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×150 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+5% AcOEt to Heptane+30% AcOEt) to yield the desired 3,4-dihydroisoquinoline as a yellow oil.

Listed in Table 34 below are 3,4-dihydroisoquinolines 16, prepared according to the above-mentioned method, with corresponding phenethylamines 18 or phenethylamines hydrochloride salt 18 as starting material.

TABLE 34 t_(R) [min] Formula LC-MS 3,4-Dihydroisoquinolines 16 MW Method MS-data m/z [M + H]⁺ 8-Bromo-5-fluoro-3,4-dihydro- C9H7NBrF 0.41 228.1 isoquinoline 226.98 LC-MS 3 8-Chloro-5-trifluoromethyl-3,4-dihydro- C10H7NClF3 0.53 233.9 isoquinoline 233.02 LC-MS 3 8-Bromo-5-chloro-3,4-dihydro- C9H7NBrCl 0.48 244.1 isoquinoline 242.95 LC-MS 3 8-Bromo-5-methoxy-3,4-dihydro- C10H10NOBr 0.48 240.1 isoquinoline 239.00 LC-MS 3 8-Bromo-5-methyl-3,4-dihydro- C10H10NBr 0.48 224.2 isoquinoline 223.00 LC-MS 3 5-Bromo-8-chloro-3,4-dihydro- C9H7NBrCl 0.49 244.1 isoquinoline 242.95 LC-MS 3 5-Bromo-8-fluoro-3,4-dihydro- C9H7NBrF 0.43 228.2 isoquinoline 226.98 LC-MS 3

Synthesis of 5-bromo-8-methoxy-3,4-dihydro-isoquinoline (C10H10NOBr, MW=239.00)

A mixture of 2-(2-bromo-5-methoxy-phenyl)-ethylamine hydrochloride (1.50 g, 4.07 mmol, 1.00 eq.) and triethylamine (1.14 mL, 8.16 mmol, 2.01 eq.) in ethyl formiate (28 mL) was refluxed for 2 hours. The solvent was removed in vacuo and the residue was partitioned between AcOEt (20 mL) and water (20 mL). The layers were separated. The org. phase was washed with water (1×20 mL), sat. aq. NaCl soln. (1×20 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give the desired formamide. The residue was stirred at 140° C. in polyphosphoric acid (22 g) for 3 hours. After cooling to r.t. the mixture was basified with 2M aq. NaOH soln. and extracted with DCM. The org. layer was then dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 23 fractions of 45 mL, Heptane+50% AcOEt to Heptane+70% AcOEt) to yield the title compound as an orange oil that solidified upon standing. LC-MS 3: t_(R)=0.50 min; [M+H]⁺=240.2

General Method for the Synthesis of the Tetrahydroisoquinoline (or the Corresponding Hydrochloride Salt) 17

To an ice-cooled solution of 8-bromo-5-fluoro-3,4-dihydro-isoquinoline (3.56 g, 15.5 mmol, 1 eq.) in MeOH (156 mL), NaBH₄ (1.22 g, 31.0 mmol, 2 eq.) was added. The mixture was stirred at 0° C. for 20 min. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo to give the desired tetrahydroisoquinoline.

The free amine was dissolved in 4M HCl in dioxane (60 mL). The resulting solid precipitate was filtered, washed with Et₂O, and dried under h.v to afford the tetrahydroisoquinoline salt as a white solid.

Listed in Table 35 below are tetrahydroisoquinolines 17 and tetrahydroisoquinoline hydrochlorides 17, prepared according to the above-mentioned method, with corresponding 3,4-dihydroisoquinolines 16 as starting material.

TABLE 35 t_(R) [min] Formula LC-MS Intermediates 17 MW Method MS-data m/z [M + H]⁺ 8-Bromo-5-fluoro-1,2,3,4-tetrahydro- C9H9NBrF 0.47 230.2 isoquinoline 228.99 LC-MS 3 8-Bromo-5-methoxy-1,2,3,4-tetrahydro- C10H12NOBr 0.52 241.9 isoquinoline 241.01 LC-MS 3 8-Bromo-5-chloro-1,2,3,4-tetrahydro- C9H9NBrCl 0.52 246.1 isoquinoline 244.96 LC-MS 3 8-Chloro-5-trifluoromethyl-1,2,3,4- C10H9NClF3 0.55 235.3 tetrahydro-isoquinoline 235.04 LC-MS 3 8-Bromo-5-methyl-1,2,3,4-tetrahydro- C10H12NBr 0.52 226.2 isoquinoline 225.02 LC-MS 3 8-Bromo-5-chloro-1,2,3,4-tetrahydro- C9H9NBrCl 0.52 246.1 isoquinoline hydrochloride 244.96 LC-MS 3 5-Bromo-8-chloro-1,2,3,4-tetrahydro- C9H9NBrCl 0.54 no ionization isoquinoline hydrochloride 244.96 LC-MS 3 8-Bromo-5-fluoro-1,2,3,4-tetrahydro- C9H9NBrF 0.48 230.1 isoquinoline hydrochloride 228.99 LC-MS 3 5-Bromo-8-fluoro-1,2,3,4-tetrahydro- C9H9NBrF 0.48 230.2 isoquinoline 228.99 LC-MS 3

General Method for the Synthesis of Boc-Protected Tetrahydroisoquinolines 7-A

To a solution of 8-chloro-5-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline (908 mg, 3.69 mmol, 1.00 eq.) and triethylamine (0.51 mL, 3.69 mmol, 1.00 eq.) in DCM (11.5 mL), a solution of di-tert-butyl dicarbonate (821 mg, 3.76 mmol, 1.02 eq.) in DCM (11.5 mL) was added under N₂. The resulting mixture was stirred at r.t. for 18 hours. The solvent was removed in vacuo and the residue was partitioned between AcOEt and water. The org. layer was washed once with water, dried over MgSO₄, filtered, and concentrated in vacuo to give the Boc-protected tetrahydroisoquinoline as a yellow oil that solidifies upon standing. The product was used without further purification.

Listed in Table 36 below are Boc-protected tetrahydroisoquinolines 7-A, prepared according to the above-mentioned method, with corresponding tetrahydroisoquinolines 17 (or the corresponding hydrochloride salt) as starting material.

TABLE 36 t_(R) [min] Formula LC-MS Intermediates 7-A MW Method MS-data m/z [M + H]⁺ 8-Chloro-5-trifluoromethyl-3,4-dihydro- C15H17NO2ClF3 1.03 no ionization 1H-isoquinoline-2-carboxylic acid tert- 335.09 LC-MS 3 butyl ester 8-Bromo-5-fluoro-3,4-dihydro-1H- C14H17NO2BrF 0.99 no ionization isoquinoline-2-carboxylic acid tert-butyl 329.04 LC-MS 3 ester

General Method for the Synthesis of Cbz-Protected Tetrahydroisoquinolines 7-A

To an ice-cooled solution of 8-bromo-5-fluoro-1,2,3,4-tetrahydro-isoquinoline (2.53 g, 10.6 mmol, 1.0 eq.) and triethylamine (4.43 mL, 31.8 mmol, 3.0 eq.) in DCM (284 mL), benzyl chloroformate (1.75 mL, 11.7 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 2 hours. The reaction was quenched with 1M aq. citric acid soln. (265 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 25 fractions of 45 mL, Heptane 100% to Heptane+15% AcOEt) to yield the Cbz-protected tetrahydroisoquinoline as a pale yellow oil.

Listed in Table 37 below are Cbz-protected tetrahydroisoquinolines 7-A, prepared according to the above-mentioned method, with corresponding tetrahydroisoquinolines (or the corresponding hydrochloride salt) 17 as starting material.

TABLE 37 t_(R) [min] Formula LC-MS Intermediates 7-A MW Method MS-data m/z [M + H]⁺ 8-Bromo-5-fluoro-3,4-dihydro-1H- C17H15NO2BrF 0.98 364.1 isoquinoline-2-carboxylic acid benzyl 363.03 LC-MS 3 ester 8-Bromo-5-methoxy-3,4-dihydro-1H- C18H18NO3Br 1.00 376.1 isoquinoline-2-carboxylic acid benzyl 375.05 LC-MS 3 ester 8-Bromo-5-chloro-3,4-dihydro-1H- C17H15NO2BrCl 1.02 380.0 isoquinoline-2-carboxylic acid benzyl 379.00 LC-MS 3 ester 8-Bromo-5-methyl-3,4-dihydro-1H- C18H18NO2Br 1.01 360.1 isoquinoline-2-carboxylic acid benzyl 359.05 LC-MS 3 ester 8-Chloro-5-trifluoromethyl-3,4-dihydro- C18H15NO2ClF3 1.03 369.8 1H-isoquinoline-2-carboxylic acid benzyl 369.07 LC-MS 3 ester 5-Bromo-8-chloro-3,4-dihydro-1H- C17H15NO2BrCl 1.02 380.0 isoquinoline-2-carboxylic acid benzyl 379.00 LC-MS 3 ester 5-Bromo-8-fluoro-3,4-dihydro-1H- C17H15NO2BrF 0.99 364.1 isoquinoline-2-carboxylic acid benzyl 363.03 LC-MS 3 ester

Synthesis of 8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C17H17NO3, MW=283.1)

To an-ice cooled suspension of 8-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (746 mg, 5.0 mmol, 1.0 eq.) and triethylamine (2.13 mL, 15.0 mmol, 3.0 eq.) in DCM (25 mL), benzyl chloroformate (0.83 mL, 5.5 mmol, 1.1 eq.) was added dropwise. The solution was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (50 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over Na₂SO₄ and concentrated in vacuo. The residue was dissolved in THF (20 mL) and 1M aq. NaOH soln. (6 mL) was added. The mixture was stirred at r.t. for 68 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×25 ml). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by CC (SiO₂, Hept/AcOEt 8:2 to 7:3) to give the title compound as a white solid.

LC-MS 2: t_(R)=0.78 min; [M+H]⁺=284.1

Synthesis of 5-bromo-8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C17H16NO3Br, MW=361.03)

A solution of 5-bromo-8-methoxy-3,4-dihydro-isoquinoline (312 mg, 1.3 mmol, 1.0 eq.) in chlorobenzene (18.4 mL) was treated with aluminium chloride (520 mg, 3.9 mmol, 3.0 eq.) and stirred at 130° C. for 1 hour. After cooling to r.t., sat. aq. NaHCO₃ soln. was added and the mixture was extracted with AcOEt (2×). The combined org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was partially purified by flashmaster (column: 25 g, flow: 30 mL/min, 25 fractions of 30 mL, AcOEt+10% MeOH) to yield a yellow oil. To an ice-cooled solution of the residue in MeOH (13.1 mL), NaBH₄ (98 mg, 2.6 mmol, 2.0 eq.) was added. The mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. To an ice-cooled solution of the residue and triethylamine (0.54 mL, 3.9 mmol, 3.0 eq.) in DCM (36 mL), benzyl chloroformate (0.21 mL, 1.43 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (36 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 27 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt). The residue was dissolved in THF (5 mL) and 1M aq. NaOH soln. (5 mL) was added. The mixture was stirred at r.t. for 18 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×10 ml). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo to give the title compound as a beige solid.

LC-MS 3: t_(R)=0.90 min; [M+H]⁺=362.2

Synthesis of 5-cyano-8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C18H16N203, MW=308.12)

To a solution of 5-bromo-8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (123 mg, 0.31 mmol, 1.0 eq.) in DMAC (0.62 mL), zinc cyanide (18 mg, 0.16 mmol, 0.5 eq.), tris(dibenzylideneacetone)dipalladium(0) (6.2 mg, 7 μmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (4.7 mg, 8 μmol, 0.03 eq.) and poly(methylhydrosiloxane) (6 μL) were added. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The reaction mixture was diluted with AcOEt and water was added. The layers were separated and the org. layer was dried over MgSO₄, filtered over celite, and concentrated in vacuo. The residue was purified by flashmaster (column: 10 g, flow: 15 mL/min, 25 fractions of 15 mL, Heptane+5% AcOEt to Heptane+40% AcOEt) to yield the title compound as a beige solid.

LC-MS 3: t_(R)=0.84 min; [M+H]⁺=309.1

Synthesis of 8-chloro-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C18H15N2O2Cl, MW=326.08)

To a solution of 5-bromo-8-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (381 mg, 1.00 mmol, 1.00 eq.) in DMAC (2 mL), zinc cyanide (59 mg, 0.50 mmol, 0.50 eq.), tris(dibenzylideneacetone)dipalladium(O) (20 mg, 0.02 mmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (15 mg, 0.03 mmol, 0.03 eq.) and poly(methylhydrosiloxane) (20 μL) were added. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The mixture was allowed to cool to r.t. To the previous mixture, zinc cyanide (59 mg, 0.50 mmol, 0.50 eq.), tris(dibenzylideneacetone)dipalladium(O) (20 mg, 0.02 mmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (15 mg, 0.03 mmol, 0.03 eq.) and poly(methylhydrosiloxane) (20 μL) were added. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The reaction mixture was diluted with AcOEt and water was added. The layers were separated and the org. layer was dried over MgSO₄, filtered over celite, and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 40 fractions of 30 mL, Heptane+5% AcOEt to Heptane+30% AcOEt) to yield the title compound as a yellow oil.

LC-MS 3: t_(R)=0.95 min; [M+H]⁺=327.0

Synthesis of 8-chloro-5-methanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C18H18NO4ClS, MW=379.07)

A mixture under Ar of 5-bromo-8-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (190 mg, 0.5 mmol, 1.0 eq.), sodium methanesulfinate (72 mg, 0.6 mmol, 1.2 eq.), L-proline (12 mg, 0.1 mmol, 0.2 eq.), 1M aq. NaOH soln. (0.1 mL, 0.1 mmol, 0.2 eq.), and copper (I) iodide (10 mg, 0.05 mmol, 0.1 eq.) in DMSO (5 mL) was stirred at 150° C. under microwave irradiations for 1 hour. The mixture was allowed to cool to r.t. and partitioned between AcOEt (125 mL), and H₂O (125 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×125 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a colorless oil.

LC-MS 3: t_(R)=0.89 min; [M+H]⁺=380.1

Synthesis of (8-Bromo-5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-((1R,2R)-2-phenyl-cyclopropyl)-methanone (C19H17NOBrF, MW=373.05)

To a solution of (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (389 mg, 2.4 mmol, 1.2 eq.) in DCM (10 mL), DIPEA (1.37 ml, 8 mmol, 4.0 eq.) and TBTU (771 mg, 2.4 mmol, 1.2 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 minutes. Then 8-bromo-5-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride (533 mg, 2.0 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in water (50 mL). The mixture was extracted with DCM (2×30 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield the title compound as a yellow oil.

LC-MS 3: t_(R)=0.96 min; [M+H]⁺=374.0

General Method for the Synthesis of Sulfonamides 37

Step 1: A mixture of 2-chloro-4-fluorobenzaldehyde (3.17 g, 20 mmol, 1.0 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1.0 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H₂O (Dean-Stark) for 2.5 hours. The mixture was concentrated in vacuo and dried under h.v. The residue was dissolved in EtOH (100 mL). The solution was cooled to 0° C. and NaBH₄ (1.14 g, 30 mmol, 1.5 eq.) was added portionwise. The cooling bath was removed and the solution was stirred at r.t. for 18 hours. The resulting reaction mixture was quenched with sat. aq. NaHCO₃ soln. (150 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo to give (2-chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine as a yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.52 min; [M+H]⁺=248.2

Step 2: To a suspension of (2-chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine (4.90 g, 19.8 mmol, 1.0 eq.) and NEt₃ (8.3 mL, 59.3 mmol, 3.0 eq.) in DCM (100 mL), a solution of p-toluenesulfonyl chloride (4.15 g, 21.8 mmol, 1.1 eq) in DCM (25 mL) was added dropwise. The solution was stirred at r.t. for 18 hours. The reaction was quenched with sat. aq. NaHCO₃ soln. (150 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane+45% AcOEt) to yield the desired sulfonamide as a colorless oil.

Listed in Table 38 below are sulfonamides 37, prepared according to the above-mentioned method, with corresponding aldehyde 34 as starting material.

TABLE 38 t_(R) [min] MS-data Formula LC-MS m/z Sulfonamides 37 MW Method [M + H]⁺ N-(2-Chloro-4-fluoro-benzyl)-N-(2,2- C18H21NO4ClFS 0.98 No dimethoxy-ethyl)-4-methyl- 401.09 LC-MS 3 ionization benzenesulfonamide N-(2-Chloro-4,5-difluoro-benzyl)-N-(2,2- C18H20NO4ClF2S 0.99 No dimethoxy-ethyl)-4-methyl- 419.08 LC-MS 3 ionization benzenesulfonamide N-(3,5-Difluoro-2-methoxy-benzyl)-N-(2,2- C19H23NO5F2S 0.97 No dimethoxy-ethyl)-4-methyl- 415.13 LC-MS 3 ionization benzenesulfonamide

General Method for the Synthesis of Isoquinolines 15-A

To a suspension of aluminiumchlorid (3.32 g, 24.9 mmol, 5 eq.) in DCM (40 mL), a solution of N-(2-chloro-4-fluoro-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzenesulfonamide (2.00 g, 4.98 mmol, 1 eq.) in DCM (15 mL) was added dropwise at r.t. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was poured on ice (300 g). The mixture was extracted with DCM (3×200 mL). The comb. org. phases were washed with sat. aq. NaHCO₃ soln. (150 mL) and sat. aq. NaCl soln. (1×100 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 30 fractions of 40 mL, Heptane to Heptane+50% AcOEt) to yield the desired isoquinoline as a brown solid.

Listed in Table 39 below are isoquinolines 15-A, prepared according to the above-mentioned method, with corresponding sulfonamide 37 as starting material.

TABLE 39 t_(R) [min] MS-data Formula LC-MS m/z Isoquinolines 15-A MW Method [M + H]⁺ 8-Chloro-6-fluoro-isoquinoline C9H5NClF 0.52 182.2 181.01 LC-MS 3 8-Chloro-5,6-difluoro-isoquinoline C9H4NClF2 0.74 200.1 199.00 LC-MS 3

Synthesis of 5,7-Difluoro-isoquinolin-8-ol (C9H5NOF2, MW=181.03)

To a suspension of aluminiumchlorid (3.85 g, 28.9 mmol, 5 eq.) in DCM (40 mL), N-(3,5-difluoro-2-methoxy-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzenesulfonamide (2.40 g, 5.78 mmol, 1 eq.) in DCM (15 mL) was added dropwise at r.t. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was poured on ice (300 g). The mixture was extracted with DCM (3×200 mL). The comb. org. phases were washed with sat. aq. NaHCO₃ soln. (150 mL) and sat. aq. NaCl soln. (1×100 mL). The resulting suspension was filtered and the solid was rinsed with DCM (20 mL). The solid was dried at h.v. to give the title compound as a yellow solid. The product was used without further purification.

LC-MS 3: t_(R)=0.42 min; [M+H]⁺=182.2

Synthesis of 8-bromo-7-fluoro-isoquinoline (C9H5NBrF, MW=224.96)

A mixture of 2-bromo-3-fluorobenzaldehyde (4.06 g, 20 mmol, 1 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H₂O (Dean-Stark) for 1 hour. The mixture was concentrated in vacuo and dried under h.v. The resulting imine was added dropwise over 20 min to hot H₂SO₄ (20 mL) at 140° C. After addition completion, the mixture was stirred at 130° C. for another 30 min. The mixture was allowed to cool to r.t., poured on ice (1 kg). Some black tar was removed by filtration over Celite. The filtrate was basified by addition of 32% aq. NaOH soln. The mixture was extracted with AcOEt (3×200 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.

LC-MS 3: t_(R)=0.58 min; [M+H]⁺=226.1

Synthesis of 3-Bromo-4-isopropoxy-benzoic acid (C10H11O3Br, MW=257.99)

Step 1: To a mixture of 3-bromo-4-hydroxybenzoic acid (4.00 g, 18.1 mmol, 1.0 eq.) and potassium carbonate anhydrous (5.49 g, 39.7 mmol, 2.2 eq.) in DMF (50 mL), 2-iodopropane (4.05 mL, 39.7 mmol, 2.2 eq.) was added. The mixture was heated at 80° C. for 18 hours. The reaction mixture was poured in water (150 mL). The mixture was extracted with AcOEt (2×200 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo to give 3-bromo-4-isopropoxy-benzoic acid isopropyl ester. The product was used without further purification

Step 2: To a solution of 3-bromo-4-isopropoxy-benzoic acid isopropyl ester (5.32 g, 17.7 mmol, 1 eq.) in EtOH (100 mL), 1M aq. NaOH soln. (80 mL) was added. The resulting solution was heated at 80° C. for 18 hours, then concentrated in vacuo. The resulting aq. layer was carefully acidified with 2N aq. HCl soln. The mixture was extracted with DCM (3×100 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo to give 3-bromo-4-isopropoxy-benzoic acid. The product was used without further purification.

LC-MS 3: t_(R)=0.80 min; [M+H]⁺=259.3

Synthesis of 3-Bromo-4-trifluoromethyl-benzoic acid (C8H4O2BrF3, MW=267.94)

3-Amino-4-(trifluoromethyl)benzoic acid (1.70 g, 8.29 mmol, 1.0 eq.) was added portionwise to a mixture of copper(II) bromide (2.78 g, 12.43 mmol, 1.5 eq.) and tert-butyl nitrite (1.48 mL, 12.43 mmol, 1.5 eq.) in MeCN (100 mL) under N₂ at r.t. A slow gas evolution started. The reaction mixture was stirred at r.t. for 1 hour. The reaction mixture was quenched with 1M aq. NaOH soln. (150 mL) and the reaction mixture was stirred at r.t. for 10 min. The blue suspension was filtered through Celite, the Celite rinsed with water. The filtrate was acidified with 2M aq. HCl soln. (150 mL) and extracted with DCM (3×100 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over Na₂SO₄ and concentrated in vacuo to give the title compound. The residue was used without further purification.

LC-MS 3: t_(R)=0.80 min; no ionization

Synthesis of 3-Bromo-4-trifluoromethoxy-benzoic acid (C8H4O3BrF3, MW=283.93)

To an ice-cooled solution of 3-bromo-4-(trifluoromethoxy)benzaldehyde (3.00 g, 11.2 mmol, 1 eq.) in MeOH (14 mL), a solution of hydrogen peroxide (30% wt solution in water, 14 mL, 11.2 mmol, 1 eq.) in 15% aq. NaOH soln. (14 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and further at r.t. for 18 hours. The reaction mixture was acidified by addition of conc. HCl. The suspension was filtered off and the filter cake was rinsed with H₂O. The resulting white solid was dried under h.v. to give the title compound. The product was used without further purification.

LC-MS 3: t_(R)=0.82 min; no ionization

General Method for the Arndt-Eistert Homoloqation of an Acid 39

Step 1: To a mixture of 3-bromo-4-chlorobenzoic acid (1.51 g, 6.4 mmol, 1.00 eq.) in DCM (25 mL) cooled at −5° C., oxalylchlorid (0.8 mL, 9.6 mmol, 1.50 eq.) and 4 drops of DMF were added. The reaction mixture was warmed to r.t. over 20 hours. The mixture was concentrated in vacuo. The resulting oil was dissolved in THF (50 mL) and cooled to −5° C. (Trimethylsilyl)diazomethane solution (2.0 M in hexanes, 7.2 mL, 14.4 mmol, 2.25 eq.) was added and the mixture was allowed to warm to r.t. over 18 hours. The mixture was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 60 fractions of 45 mL, Heptane to Heptane+20% AcOEt) to yield 1-(3-bromo-4-chloro-phenyl)-2-diazo-ethanone as a yellow solid.

Step 2: To a solution of 1-(3-bromo-4-chloro-phenyl)-2-diazo-ethanone (877 mg, 3.38 mmol, 1.0 eq.) in MeOH (30 mL), a solution of silver benzoate (464 mg, 2.03 mmol, 0.6 eq.) in triethylamine (7.0 mL) was added dropwise. The resulting black solution was stirred at r.t. for 19 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt (100 mL) and washed with sat. aq. NH₄Cl soln. (3×50 mL), sat. aq. NaCl soln. (2×50 mL), dried over MgSO₄, and concentrated in vacuo. The product was purified by flashmaster (column: 100 g, flow: 45 mL/min, 60 fractions of 45 mL, Heptane to Heptane+20% AcOEt) to yield (3-bromo-4-chloro-phenyl)-acetic acid methyl ester as a yellow solid.

Listed in Table 40 below are phenylacetic acid ester 9-A, prepared according to the above-mentioned method, with corresponding acid 39 and the corresponding alcohol (step 2) as starting materials.

TABLE 40 t_(R) [min] Formula LC-MS MS-data Phenylacetic acid ester 9-A MW Method m/z [M + H]⁺ (3-Bromo-4-chloro-phenyl)-acetic acid C9H8O2BrCl 0.84 no ionization methyl ester 261.94 LC-MS 2 (3-Bromo-5-chloro-phenyl)-acetic acid C10H10O2BrCl 0.92 no ionization ethyl ester 275.96 LC-MS 3 (3-Bromo-4-trifluoromethyl-phenyl)- C10H8O2BrF3 0.90 no ionization acetic acid methyl ester 295.97 LC-MS 3 (3-Bromo-4-methyl-phenyl)-acetic C10H11O2Br 0.88 no ionization acid methyl ester 241.99 LC-MS 3 (3-Bromo-2-fluoro-phenyl)-acetic acid C10H10O2BrF 0.87 no ionization ethyl ester 259.99 LC-MS 3 (3-Bromo-5-methoxy-phenyl)-acetic C11H13O3Br 0.89 no ionization acid ethyl ester 272.01 LC-MS 3 (5-Bromo-2-chloro-phenyl)-acetic acid C9H8O2BrCl 0.83 no ionization methyl ester 261.94 LC-MS 2 (5-Bromo-2-fluoro-phenyl)-acetic acid C9H8O2BrF 0.78 no ionization methyl ester 245.97 LC-MS 2 (3-Bromo-4-trifluoromethoxy-phenyl)- C11H10O3BrF3 0.96 no ionization acetic acid ethyl ester 325.98 LC-MS 3 (3-Bromo-4-methanesulfonyl-phenyl)- C11H13O4BrS 0.76 no ionization acetic acid ethyl ester 319.97 LC-MS 3 (3-Bromo-4-isopropoxy-phenyl)-acetic C13H17O3Br 0.95 no ionization acid ethyl ester 300.04 LC-MS 3 (8-Chloro-2,3-dihydro- C12H13O4Cl 0.85 no ionization benzo[1,4]dioxin-6-yl)-acetic acid 256.05 LC-MS 3 ethyl ester (7-Chloro-benzo[1,3]dioxol-5-yl)- C11H11O4Cl 0.86 no ionization acetic acid ethyl ester 242.04 LC-MS 3 (4-Bromo-3-fluoro-phenyl)-acetic acid C10H10O2BrF 0.88 no ionization ethyl ester 259.99 LC-MS 3 (4-Bromo-2-chloro-phenyl)-acetic acid C10H10O2BrCl 0.92 no ionization ethyl ester 275.96 LC-MS 3 (4-Bromo-3-chloro-phenyl)-acetic acid C10H10O2BrCl 0.91 no ionization ethyl ester 275.96 LC-MS 3 (4-Bromo-3-methoxy-phenyl)-acetic C11H13O3Br 0.87 no ionization acid ethyl ester 272.01 LC-MS 3 (3-Bromo-4-tert-butoxy-phenyl)-acetic C14H19O3Br 0.97 no ionization acid ethyl ester 314.05 LC-MS 3 (3-Bromo-4-difluoromethoxy-phenyl)- C11H11O3BrF2 0.90 no ionization acetic acid ethyl ester 307.99 LC-MS 3 (4-Bromo-3-ethoxy-phenyl)-acetic C12H15O3Br 0.91 no ionization acid ethyl ester 286.02 LC-MS 3 [4-Bromo-3-(2,2,2-trifluoro-ethoxy)- C12H12O3BrF3 0.95 no ionization phenyl]-acetic acid ethyl ester 339.99 LC-MS 3

General Method for the Esterification of an Acid

A solution of (3-bromo-4-methoxy-phenyl)-acetic acid (2.5 g, 10 mmol, 1 eq) in 1.25M HCl in ethanol (13 mL) was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between DCM (25 mL) and 1M aq. NaOH (25 mL). The layers were separated. The aq. phase was extracted with DCM (2×25 mL). The comb. org. phases were washed with water (1×25 mL), dried over MgSO₄, and concentrated in vacuo to give the desired ester as a pale yellow oil. The product was used without further purification.

Listed in Table 41 below are phenylacetic acid ester 9, prepared according to the above-mentioned method, with corresponding acid as starting material.

TABLE 41 t_(R) [min] Formula LC-MS MS-data Phenylacetic acid ester 9 MW Method m/z [M + H]⁺ (3-Bromo-4-methoxy-phenyl)-acetic C11H13O3Br 0.81 no ionization acid ethyl ester 272.01 LC-MS 2 (3-Bromo-4-fluoro-phenyl)-acetic acid C10H10O2BrF 0.85 no ionization ethyl ester 259.99 LC-MS 2 (3-Bromo-5-fluoro-phenyl)-acetic acid C10H10O2BrF 0.89 no ionization ethyl ester 259.99 LC-MS 3 (5-Bromo-2-methoxy-phenyl)-acetic C11H13O3Br 0.88 273.2 acid ethyl ester 272.01 LC-MS 3 (2-Bromo-phenyl)-acetic acid ethyl C10H11O2Br 0.86 no ionization ester 241.99 LC-MS 3 (2-Bromo-4-chloro-phenyl)-acetic acid C10H10O2BrCl 0.91 no ionization ethyl ester 275.96 LC-MS 3 (2-Bromo-4-methoxy-phenyl)-acetic C11H13O3Br 0.87 no ionization acid ethyl ester 272.01 LC-MS 3

General Method for the Transesterification of an Ester

A solution of (5-bromo-2-chloro-phenyl)-acetic acid methyl ester (1.04 g, 3.93 mmol, 1 eq.) in 1.25M HCl in ethanol (30 mL) was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The product was used without further purification.

Listed in Table 42 below are phenylacetic acid ester 9, prepared according to the above-mentioned method, with corresponding ester as starting material.

TABLE 42 t_(R) [min] MS-data Formula LC-MS m/z Phenylacetic acid ester 9 MW Method [M + H]⁺ (5-Bromo-2-chloro-phenyl)- C10H10O2BrCl 0.89 no ionization acetic acid ethyl ester 275.96 LC-MS 2 (5-Bromo-2-fluoro-phenyl)- C10H10O2BrF 0.84 no ionization acetic acid ethyl ester 259.99 LC-MS 2

Synthesis of 1-(3-chloro-4-methoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (C13H15O3Cl, MW=254.07)

Step 1: To a suspension of potassium tert-butoxide (2.36 g, 20 mmol, 4 eq.) in THF (15 mL), a solution of tosylmethyl isocyanide (1.95 g, 10 mmol, 2 eq.) in THF (5 mL) was added at −78° C. The mixture was stirred at −78° C. for 15 min. A solution of 3-chloro-4-methoxybenzaldehyde (879 mg, 5 mmol, 1 eq.) in THF (5 mL) was added dropwise. The resulting mixture was stirred for 1.5 hours at −78° C. To the cooled reaction mixture, methanol (5 mL) was added. The mixture was then heated at reflux for 30 min. The solvent was removed in vacuo. The residue was partitioned between water (20 mL) and AcOEt (10 mL). The aq. phase was extracted with AcOEt (2×10 mL). The comb. org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 50 fractions of 45 mL, Heptane to Heptane+25% AcOEt) to yield (3-chloro-4-methoxy-phenyl)-acetonitrile as a pale yellow oil that solidified upon standing.

LC-MS 3: t_(R)=0.78 min; [M+H]⁺=no ionization

Step 2: A mixture of (3-chloro-4-methoxy-phenyl)-acetonitrile (320 mg, 1.76 mmol, 1.00 eq.), 1-bromo-2-chloro ethane (0.51 mL, 6.05 mmol, 3.40 eq.) and benzyltriethylammonium chloride (10 mg, 0.04 mmol, 0.02 eq.) was heated at 70° C. 50% aq. NaOH soln (1.5 mL) was slowly added and the reaction mixture was stirred at 70° C. for 18 hours. 1-Bromo-2-chloro ethane (0.26 mL, 3.03 mmol, 1.72 eq.) and a spatula tip of benzyltriethylammonium chloride were added again and the mixture was stirred at 70° C. for 3 hours. 50% aq. NaOH soln. (1.5 mL) and water (5 mL) were added and the mixture was then heated up to 130° C. and stirred at that temperature for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with water (20 mL) and extracted once with AcOEt (20 mL) and once with DCM (20 mL). The basic aq. layer was acidified with conc. HCl (pH<1). The resulting precipitate was filtered and washed with 1M aq. HCl soln. The filter cake was then redissolved in DCM (20 mL) and washed with 1M HCl soln (2×20 mL) and sat. aq. NaCl soln (1×20 mL). The org. layer was dried over MgSO₄, filtered, and concentrated in vacuo to give 1-(3-chloro-4-methoxy-phenyl)-cyclopropanecarboxylic acid as a yellow solid. The product was used without further purification.

LC-MS 3: t_(R)=0.75 min; [M+H]⁺=no ionization

Step 3: A solution of 1-(3-chloro-4-methoxy-phenyl)-cyclopropanecarboxylic acid (250 mg, 0.96 mmol, 1 eq.) in 1.25M HCl in EtOH (2.4 mL) was stirred at r.t. for 2 hours and further at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to yield the title compound as a colorless oil. LC-MS 3: t_(R)=0.91 min; [M+H]⁺=255.2

Synthesis of (±)-2-(3-Bromo-4-methoxy-phenyl)-propionic acid ethyl ester (C12H15O3Br, MW=286.02)

To an ice-cooled solution of (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (1.45 g, 5.12 mmol, 1.00 eq.) in THF (18 mL), sodium hydride (60% dispersion in mineral oil, 225 mg, 5.63 mmol, 1.10 eq.) was added. The reaction mixture was stirred at r.t. for 30 min. Iodomethane (0.34 mL, 5.38 mmol, 1.05 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. Water was carefully added. THF was removed in vacuo. The residue was extracted with AcOEt (2×). The org. layer was dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 25 fractions of 40 mL, Heptane 100% to Heptane+15% AcOEt) to yield the title compound as a yellow oil.

LC-MS 3: t_(R)=0.90 min; [M+H]⁺=287.2

Synthesis of (8-Bromo-5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-((1R,2R)-2-phenyl-cyclopropyl)-methanone (C19H17NOBrF, MW=373.05)

A solution of 8-bromo-5-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride (200 mg, 0.75 mmol, 1.0 eq.) and the acid (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (122 mg, 0.75 mmol, 1.0 eq.) in DMF (9 mL) was treated with 4-(dimethylamino)pyridine (367 mg, 3.00 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (216 mg, 1.13 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt (70 mL). The diluted solution was washed with 1N aq. HCl (3×30 mL), sat. aq. NaCl soln. (1×30 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give the desired compound as a pale yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.97 min; [M+H]⁺=374.0

Synthesis of 3-Bromo-4-isopropoxy-phenol (C9H11O2Br, MW=229.99)

Step 1: To a solution of hydroquinone (3.37 g, 30.0 mmol, 1.00 eq.) and 2-iodopropane (2 mL, 19.8 mmol, 0.66 eq.) in EtOH (12 mL), a solution of KOH (1.68 g, 30.0 mmol, 1.00 eq.) in water (6 mL) was added. The dark brown solution was refluxed for 18 hours. The solvent was removed in vacuo and the remaining aq. phase was acidified with 2M aq. HCl soln. and extracted with AcOEt (3×15 mL). The comb. org. layers were washed with sat. aq. NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 340 g, flow: 90 mL/min, 100 fractions of 45 mL, Heptane to Heptane+35% AcOEt) to yield 4-isopropoxy-phenol as an orange oil.

LC-MS 3: t_(R)=0.67 min; [M+H]⁺=No ionization

Step 2: To a solution of 4-isopropoxy-phenol (800 mg, 5.26 mmol, 1.0 eq.) and triethylamine (1.47 mL, 10.5 mmol, 2.0 eq.) in DCM (22 mL), acetyl chloride (0.45 mL, 6.36 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred at r.t. for 4 days. Sat. aq. NaHCO₃ soln. was added and the layers were separated. The org. phase was dried over MgSO₄, filtered, and concentrated in vacuo to give acetic acid 4-isopropoxy-phenyl ester as a yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.83 min; [M+H]⁺=No ionization

Step 3: To a solution of acetic acid 4-isopropoxy-phenyl ester (1.04 g, 5.35 mmol, 1 eq.) in MeCN (22 mL), N-bromsuccinimide (953 mg, 5.35 mmol, 1 eq.) was added. The resulting mixture was stirred at r.t. for 18 hours. The solvent was removed in vacuo. The residue was partitioned between water and Et₂O. The org. layer was dried over MgSO₄, filtered, and concentrated in vacuo to give acetic acid 3-bromo-4-isopropoxy-phenyl ester as an orange oil. The product was used without further purification.

LC-MS 3: t_(R)=0.90 min; [M+H]⁺=No ionization

Step 4: To a solution of acetic acid 3-bromo-4-isopropoxy-phenyl ester (1.44 g, 4.98 mmol, 1.00 eq.) in MeOH (20 mL), a solution of KOH (303 mg, 5.39 mmol, 1.08 eq.) in H₂O (3 mL) was added. The resulting mixture was stirred at r.t. for 45 min. Water (5 mL) was added and the mixture was acidified with 2N aq. HCl soln. then extracted with DCM (3×). The comb. org. layers were dried over MgSO₄, filtered, and concentrated in vacuo to give the title compound as a brown oil. The product was used without purification.

LC-MS 3: t_(R)=0.79 min; [M+H]⁺=230.1

General Method for the Alkylation of a Phenol 40

To a mixture of 3-bromo-4-isopropoxy-phenol (1.22 g, 4.86 mmol, 1.0 eq.) and K₂CO₃ (2.01 g, 14.6 mmol, 3.0 eq.) in DMF (17.5 mL), ethyl bromoacetate (0.81 mL, 7.29 mmol, 1.5 eq.) was added. The mixture was stirred at r.t. for 18 hours. The reaction mixture was partitioned between AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. extracts were washed with water and sat. aq. NaCl, dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+20% AcOEt) to give the desired product as a colorless oil.

Listed in Table 43 below are phenoxyacetic acid ester 9-B, prepared according to the above-mentioned method, with corresponding phenol 40 and the corresponding bromide as starting material.

TABLE 43 t_(R) [min] Formula LC-MS MS-data Phenoxyacetic acid ester 9-B MW Method m/z [M + H]⁺ (3-Bromo-4-isopropoxy-phenoxy)- C13H17O4Br 0.93 no ionization acetic acid ethyl ester 316.03 LC-MS 3 (3-Bromo-4-trifluoromethoxy- C11H10O4BrF3 0.95 no ionization phenoxy)-acetic acid ethyl ester 341.97 LC-MS 3 2-(3-Bromo-4-methoxy-phenoxy)- C12H15O4Br 0.89 303.1 propionic acid ethyl ester 302.02 LC-MS 3 2-(3-Bromo-4-methoxy-phenoxy)- C13H17O4Br 0.93 316.9 butyric acid ethyl ester 316.03 LC-MS 3 2-(3-Bromo-4-methoxy-phenoxy)-2- C13H17O4Br 0.92 316.9 methyl-propionic acid ethyl ester 316.03 LC-MS 3 (2-Bromo-3-methoxy-phenoxy)-acetic acid C11H13O4Br 0.84 288.9 ethyl ester 288.00 LC-MS 3

Synthesis of (3-Bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (C10H11O3Br, MW=257.90)

To a solution of 3-bromo-4-hydroxyphenylacetic acid (1.19 g, 5 mmol, 1 eq.) in EtOH (15 mL), thionyl chloride (0.73 mL, 10 mmol, 2 eq.) was added. The reaction mixture was stirred at r.t. during 1 h 30. The mixture was concentrated in vacuo. The residue was partitioned between DCM (50 mL) and sat. aq. NaHCO₃ soln. (50 mL). The layers were separated and the aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo to give the title compound as a pale yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.76 min; [M+H]⁺=259.3

General Method for the Alkylation of a Phenol

Method A: To a solution of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (135 mg, 0.5 mmol, 1.0 eq.) and K₂CO₃ (207 mg, 1.5 mmol, 3.0 eq.) in DMF (1.8 mL), iodoethane (61 μL, 0.8 mmol, 1.5 eq.) was added. The mixture was stirred at 60° C. for 18 hours. The reaction mixture was partitioned between DCM and water. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. extracts were concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo.

Listed in Table 44 below are compound 9-C, prepared according to the above-mentioned method, with corresponding halogen as starting material.

TABLE 44 t_(R) [min] Formula LC-MS MS-data Compound 9 MW Method m/z [M + H]⁺ (3-Bromo-4-ethoxy-phenyl)-acetic acid C12H15O3Br 0.91 286.9 ethyl ester 286.02 LC-MS 3 (3-Bromo-4-cyclopropylmethoxy- C14H17O3Br 0.95 312.9 phenyl)-acetic acid ethyl ester 312.04 LC-MS 3 (3-Bromo-4-propoxy-phenyl)-acetic acid C13H17O3Br 0.96 300.9 ethyl ester 300.04 LC-MS 3 (3-Bromo-4-isobutoxy-phenyl)-acetic C14H19O3Br 1.00 314.9 acid ethyl ester 314.05 LC-MS 3 [3-Bromo-4-(2-methoxy-ethoxy)- C13H17O4Br 0.87 316.9 phenyl]-acetic acid ethyl ester 316.03 LC-MS 3 [3-Bromo-4-(2-fluoro-ethoxy)-phenyl]- C12H14O3BrF 0.88 no ionization acetic acid ethyl ester 304.01 LC-MS 3

Method B: Synthesis of [3-Bromo-4-(2,2-difluoro-ethoxy)-phenyl]acetic acid ethyl ester (C12H13O3BrF2, MW=322.00): Sodium hydride 60% dispersion in mineral oil (80 mg, 2.0 mmol, 1.0 eq.) was added portionwise to an ice-cooled solution of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (564 mg, 2.0 mmol, 1.0 eq.) in THF (9.4 mL). The ice bath was removed and the mixture was allowed to warm to r.t. and stirred for 30 min. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (961 mg, 4.4 mmol, 2.2 eq.) in THF (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was taken up in DCM and water was added. The layers were separated and the aq. phase was extracted with DCM (3×). The comb. org. layers were washed with sat. aq. NaCl soln., dried over MgSO₄, filtered and concentrated in vacuo to give the title compound as a yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.90 min; [M+H]⁺=no ionization

Method C: Synthesis of [3-bromo-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (C12H12O3BrF3, MW=339.99): 1,1,1-Trifluoro-2-iodoethane (0.15 mL, 1.5 mmol, 1 eq.) was added to a solution of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (456 mg, 1.5 mmol, 1 eq.) and potassium carbonate (622 mg, 4.5 mmol, 3 eq.) in DMF (1.5 mL). The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The reaction mixture was diluted with DCM and water. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+AcOEt 20%) to yield the title compound as a colorless oil.

LC-MS 3: t_(R)=0.94 min; [M+H]⁺=no ionization

Synthesis (±)-2-(4-Bromo-3-methoxy-phenoxy)-propionic acid methyl ester (C11H13O4Br, MW=288.00)

4-Bromo-3-methoxyphenol (209 mg, 1 mmol, 1 eq.) was dissolved in MeCN (4 mL). (±)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (258 mg, 1 mmol, 1 eq.) and K₂CO₃ (276 mg, 2 mmol, 2 eq.) were added and the mixture was stirred at 65° C. for 6 hours and further at r.t. for 4 days. The mixture was partitioned between water and Et₂O. The layers were separated and the aq. phase was extracted with Et₂O (2×). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to the title compound as a colorless oil.

LC-MS 3: t_(R)=0.87 min; [M+H]⁺=289.0

Synthesis of (4-chloro-3-isopropoxy-phenyl)-acetic acid tert-butyl ester (C15H21O3Cl, MW=284.12)

Step 1: To a solution of 5-bromo-2-chlorophenol (2.08 g, 10 mmol, 1.0 eq.) and potassium carbonate (4.15 g, 30 mmol, 3.0 eq.) in MeCN (19 mL), 2-iodopropane (1.53 mL, 15 mmol, 1.5 eq.) was added. The mixture was stirred at r.t. for 18 hours. The mixture was heated up to 50° C. and stirred at that temperature for 2.5 hours. The reaction mixture was partitioned between AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. extracts were washed with water and sat. aq. NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo to give 4-bromo-1-chloro-2-isopropoxy-benzene as a yellow oil. The product was used without further purification. LC-MS 3: t_(R)=0.98 min; [M+H]⁺=no ionization

Step 2: To a solution of 4-bromo-1-chloro-2-isopropoxy-benzene (2.48 g, 9.8 mmol, 1.0 eq.) and bis(tri-tert-butylphosphine)palladium(O) (501 mg, 0.98 mmol, 0.1 eq.) in dioxane (84 mL), a 0.5M solution of 2-tert-butoxy-2-oxoethylzinc chloride in Et₂O (35.3 mL, 17.6 mmol, 1.8 eq.) was added. The resulting mixture was stirred at r.t. for 2 days. The mixture was filtered over celite and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+8% AcOEt) to yield the title compound as a colorless oil.

LC-MS 3: t_(R)=1.01 min; [M+H]⁺=no ionization

Synthesis of (3-chloro-4-cyclopropoxy-phenyl)-acetic acid tert-butyl ester (C15H19O3Cl, MW=282.10)

Step 1: Potassium carbonate (8.29 g, 60 mmol, 3.0 eq.) and 2-chloroethyl p-toluenesulfonate (5.16 g, 22 mmol, 1.1 eq.) were added in sequence to a solution of 4-bromo-2-chlorophenol (4.19 g, 20 mmol, 1.0 eq.) in DMF (25 mL). The resulting mixture was heated up to 60° C. and stirred at that temperature for 4 hours. The mixture was allowed to cool down to r.t. and was partitioned between AcOEt (290 mL) and water (120 mL). The layers were separated. The org. phase was washed with water (4×120 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give 4-bromo-2-chloro-1-(2-chloro-ethoxy)-benzene as a colorless oil that solidified upon standing. The product was used without further purification.

LC-MS 3: t_(R)=0.93 min; [M+H]⁺=no ionization

Step 2: To a solution of 4-bromo-2-chloro-1-(2-chloro-ethoxy)-benzene (5.84 g, 17.4 mmol, 1 eq.) in DMF (22 mL), sodium hydride 60% dispersion in mineral oil (1.40 g, 34.9 mmol, 2 eq.) was added portionwise at r.t. The resulting mixture was stirred at r.t. for 18 hours. The mixture was partitioned between water (70 mL) and AcOEt (250 mL). The layers were separated and the org. layer was washed with water (4×100 mL), dried over MgSO₄, filtered, and concentrated in vacuo. To a solution of the residue in DMF (22 mL), sodium hydride 60% dispersion in mineral oil (1.40 g, 34.9 mmol, 2 eq.) was added portionwise at r.t. The resulting mixture was stirred at r.t. for 48 hours. The mixture was partitioned between water (70 mL) and AcOEt (250 mL). The layers were separated and the org. layer was washed with water (4×100 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+5% AcOEt) to give 4-bromo-2-chloro-1-vinyloxy-benzene as a colorless oil.

LC-MS 3: t_(R)=0.93 min; [M+H]⁺=no ionization

Step 3: To an ice-cooled solution of diethylzinc solution (1.0 M in hexanes) (8.25 mL, 8.25 mmol, 2.75 eq.) in DCM (15 mL), trifluoroacetic acid (0.6 mL, 7.80 mmol, 2.60 eq.) was added slowly (gas evolution). Upon addition completion, the mixture was stirred at 0° C. for 10 min. Methyleniodid (0.7 mL, 8.70 mmol, 2.90 eq.) was added dropwise and the mixture was stirred at 0° C. for 10 min. A solution of 4-bromo-2-chloro-1-vinyloxy-benzene (700 mg, 3.00 mmol, 1.00 eq.) in DCM (5 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 1 hour, then quenched with 2N aq. HCl soln. (15 mL) and water (5 mL). The layers were separated. The aq. layer was extracted with DCM (1×25 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+5% AcOEt) to yield 4-bromo-2-chloro-1-cyclopropoxy-benzene as a colorless oil.

LC-MS 3: t_(R)=0.95 min; [M+H]⁺=no ionization

Step 4: To a solution of 4-bromo-2-chloro-1-cyclopropoxy-benzene (610 mg, 2.46 mmol, 1.00 eq.) in dioxane (20 mL), bis(tri-t-butylphosphine)palladium (0) (193 mg, 0.37 mmol, 0.15 eq.) and 2-tert-butoxy-2-oxoethylzinc chloride (0.5M in diethyl ether) (8.9 mL, 4.44 mmol, 1.80 eq.) were added in sequence. The resulting mixture was stirred at r.t. for 18 hours and further at 60° C. for 4 hours. The mixture was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane+5% AcOEt) to yield the title compound as a white solid.

LC-MS 3: t_(R)=0.98 min; [M+H]⁺=no ionization

Synthesis of (3-bromo-4-dimethylamino-phenyl)-acetic acid ethyl ester (C12H16NO2Br, MW=285.04)

Step 1: To a solution of ethyl 4-aminophenylacetate (1.79 g, 10 mmol, 1 eq.) in MeCN (50 mL), N-bromsuccinimide (1.78 g, 10 mmol, 1 eq.) was added slowly. The mixture was stirred at r.t. for 72 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (50 mL) and Et₂O (50 mL). The org. phase was washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo to give (4-amino-3-bromo-phenyl)-acetic acid ethyl ester as an orange oil. The product was used without further purification.

LC-MS 3: t_(R)=0.77 min; [M+H]⁺=257.9

Step 2: To a solution of (4-amino-3-bromo-phenyl)-acetic acid ethyl ester (2.56 g, 9.9 mmol, 1.0 eq.) in formic acid (1.89 mL, 49.6 mmol, 5.0 eq.), 37% wt aqueous formaldehyde solution (1.7 mL, 21.8 mmol, 2.2 eq.) was added. The mixture was stirred at 90° C. for 4 hours. The mixture was allowed to cool down to r.t. and partitioned between sat. aq. NaHCO₃ soln. (75 mL) and DCM (75 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vcacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Hept/AcOEt-NEt₃ (10% NEt₃) 95:5 to Hept/AcOEt-NEt₃ (10% NEt₃) 8:2) to yield the title compound as an yellow oil.

LC-MS 3: t_(R)=0.68 min; [M+H]⁺=286.1

Synthesis of (3-bromo-2-methoxy-phenyl)-acetic acid methyl ester (C10H11O3Br, MW=257.99)

Step 1: To a solution of tert-butylamine (1.74 mL, 16.4 mmol, 1.50 eq.) in toluene (54 mL), bromine (0.47 mL, 9.2 mmol, 0.84 eq.) was added dropwise at −30° C. The mixture was stirred at −30° C. for 1 hour then cooled down to −78° C. and a solution of methyl 2-(2-hydroxyphenyl)acetate (1.82 g, 11.0 mmol, 1.00 eq.) in DCM (10 mL) was slowly added. The resulting mixture was stirred at r.t. for 18 hours. Water was added and the layers were separated. The aq. phase was extracted with DCM (2×). The comb. org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give (3-bromo-2-hydroxy-phenyl)-acetic acid methyl ester as a pale yellow oil that solidified upon standing.

LC-MS 3: t_(R)=0.74 min; [M+H]⁺=no ionization

Step 2: To a solution of (3-bromo-2-hydroxy-phenyl)-acetic acid methyl ester (866 mg, 3.5 mmol, 1 eq.) and potassium carbonate (2.44 g, 17.7 mmol, 5 eq.) in MeCN (9 mL), iodomethane (0.67 mL, 10.6 mmol, 3 eq.) was added. The resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. layers were dried over MgSO₄, filtered, and concentrated in vacuo to give the title compound as an orange oil. The product was used without further purification.

LC-MS 3: t_(R)=0.83 min; [M+H]⁺=259.1

Synthesis of (2-chloro-3-methoxy-phenyl)-acetic acid ethyl ester (C11H13O3Cl, MW=228.06)

Step 1: To a solution of 2-chloro-3-methoxybenzaldehyde (1.74 g, 10.0 mmol, 1.0 eq.) and methyl(methylsulfinyl)methyl sulfide (1.72 mL, 16.1 mmol, 1.6 eq.) in THF (9 mL), benzyltrimethylammonium hydroxide solution in methanol (2.3 mL, 10.0 mmol, 1.0 eq.) was added. The resulting solution was refluxed for 18 hours. The solvent was removed in vacuo. The residue was taken up in AcOEt and washed with 1M aq. HCl soln., water, and sat. aq. NaCl soln. The org. layer was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+20% AcOEt to Heptane+65% AcOEt) to yield 2-chloro-1-((E)-2-methanesulfinyl-2-methylsulfanyl-vinyl)-3-methoxy-benzene as a pale orange oil.

LC-MS 3: t_(R)=0.79 min; [M+H]⁺=277.1

Step 2: To a solution of 2-chloro-1-((E)-2-methanesulfinyl-2-methylsulfanyl-vinyl)-3-methoxy-benzene (400 mg, 1.26 mmol, 1 eq.) in EtOH (2 mL), 1.25M hydrogen chloride in ethanol (2 mL) was added and the resulting solution was refluxed for 2 hours. The solvent was removed in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 35 fractions of 40 mL, Heptane 100% to Hept.+20% AcOEt) to yield the title compound as a colorless oil.

LC-MS 3: t_(R)=0.84 min; [M+H]⁺=no ionization

Synthesis of (3-hydroxy-4-propyl-phenyl)-acetic acid tert-butyl ester (C15H22O3, MW=250.16)

Step 1: To a suspension of ethyltriphenylphosphonium bromide (8.44 g, 22 mmol, 2.2 eq.) in toluene (60 mL), a solution of potassium tert-butoxide (2.60 g, 22 mmol, 2.2 eq.) in THF (15 mL) was added dropwise. The resulting red mixture was stirred at r.t. for 4 hours. The mixture was then cooled to −78° C. and a solution of 4-bromo-2-hydroxybenzaldehyde (2.12 mg, 10 mmol, 1.0 eq.) in toluene (10 mL) was added dropwise. The resulting solution was allowed to slowly warm to r.t. and further stirred at r.t. for 20 hours. The reaction was quenched with sat. aq. NH₄Cl soln. (30 mL). The mixture was diluted with water (30 mL). The layers were separated and the aq. phase was extracted with Et₂O (3×30 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane/AcOEt 8:2) to yield 5-bromo-2-(propenyl)-phenol as a yellow oil as an unseparable mixture of E- and Z-isomer (ca. 85:15).

LC-MS 3: t_(R)=0.85 min; [M+H]⁺=no ionization

Step 2: A solution of 5-bromo-2-(propenyl)-phenol (mixture of E- and Z-isomer ca. 85:15) (1.10 g, 4.99 mmol, 1.0 eq.) in DMF (15 mL) was slowly added to sodium hydride 60% dispersion in mineral oil (261 mg, 6.52 mmol, 1.3 eq.) at 0° C. under N₂. Upon completion of the addition, the mixture was allowed to warm to r.t. Benzyl bromide (0.61 mL, 4.99 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. AcOEt was added and the reaction was stirred at r.t. for 30 min. Water was added to the mixture. The layers were separated and the org. phase was washed with water and sat. aq. NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield 2-benzyloxy-4-bromo-1-(propenyl)-benzene as a pale yellow oil as an unseparable mixture of E- and Z-isomers (ca. 9/1).

LC-MS 3: t_(R)=1.05 min; [M+H]⁺=no ionization

Step 3: A solution of 2-tert-butoxy-2-oxoethylzinc chloride (12.2 mL, 6.13 mmol, 1.8 eq.) was added to a solution of 2-benzyloxy-4-bromo-1-(propenyl)-benzene (mixture of E- and Z-isomers ca. 9:1) (1.17 g, 3.40 mmol, 1.00 eq.) and bis(tri-tert-butylphosphine)palladium(0) (266 mg, 0.51 mmol, 0.15 eq.) in dioxane (27 mL). The resulting mixture was stirred at r.t. for 18 hours. The mixture was filtered through Celite and the filter cake was rinced with dioxane. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+12% AcOEt) to yield [3-benzyloxy-4-(propenyl)-phenyl]-acetic acid tert-butyl ester as a pale yellow oil.

LC-MS 3: t_(R)=1.07 min; [M+H]⁺=339.1

Step 4: To a solution of [3-benzyloxy-4-(propenyl)-phenyl]-acetic acid tert-butyl ester (1.21 g, 3.21 mmol, 1 eq.) in THF (39 mL) under N₂, palladium on activated carbon (10% wt., 121 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The black suspension was filtered through Celite and the filter cake was rinsed with THF. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 50 fractions of 45 mL, Heptane 100% to Heptane+20% AcOEt) to yield the title compound as a colorless oil.

LC-MS 3: t_(R)=0.93 min; [M+H]⁺=no ionization

Synthesis of (4-hydroxy-3-isopropyl-phenyl)-acetic acid tert-butyl ester (C15H22O3, MW=250.16)

Step 1: To a solution of 2-isopropylphenol (1.39 mL, 10 mmol, 1 eq.) in DCM (8 mL), bromine (0.52 mL, 10 mmol, 1 eq.) was added at r.t. over a period of 10 min. The reaction mixture was stirred at r.t. for 18 hours. The mixture was poured into a mixture of sat. aq. NaHCO₃ soln. (25 mL) and ice. The resulting mixture was extracted with AcOEt (2×25 mL). The comb. org. layers were washed successively with water (25 mL) and sat. aq. NaCl soln. (25 mL), then dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield 4-bromo-2-isopropyl-phenol as a pale yellow oil.

LC-MS 3: t_(R)=0.87 min; [M+H]⁺=no ionization

Step 2: A solution of 4-bromo-2-isopropyl-phenol (1.98 g, 9.1 mmol, 1.0 eq.) in DMF (27 mL) was slowly added to sodium hydride 60% dispersion in mineral oil (476 mg, 11.9 mmol, 1.3 eq.) at 0° C. under N₂. Upon completion of the addition, the mixture was allowed to warm to r.t. Benzyl bromide (1.1 mL, 9.1 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. AcOEt was added and the reaction was stirred for 30 min. Water was added to the mixture. The layers were separated and the org. phase was washed with water and sat. aq. NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo. To a solution of the residue in dioxane (75 mL), a solution of 2-tert-butoxy-2-oxoethylzinc chloride (33.9 mL, 17 mmol, 1.8 eq.) and bis(tri-tert-butylphosphine)palladium(0) (739 mg, 1.42 mmol, 0.15 eq) were added. The resulting mixture was stirred at r.t. for 18 hours. The mixture was filtered through Celite and the filter cake was rinced with dioxane. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+12% AcOEt) to yield (4-benzyloxy-3-isopropyl-phenyl)-acetic acid tert-butyl ester as a colorless oil.

LC-MS 3: t_(R)=1.08 min; [M+H]⁺=no ionization

Step 3: To a solution of (4-benzyloxy-3-isopropyl-phenyl)-acetic acid tert-butyl ester (3.04 g, 8.16 mmol, 1 eq) in THF (99 mL) under N₂, palladium on activated carbon (10 wt. % 304 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 2 days. The black suspension was filtered through Celite and the filter cake was rinsed with THF. The filtrate was concentrated in vacuo to give the title compound as a colorless oil. The product was used without further purification.

LC-MS 3: t_(R)=0.91 min; [M+H]⁺=no ionization

General Method for the Synthesis of Pinacol Boronic Esters 8 or 11

To a solution under N₂ of (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (10.90 g, 39.9 mmol, 1.00 eq.) in DMSO (100 mL), bis(pinacolato)diboron (12.41 g, 47.9 mmol, 1.20 eq.), potassium acetate (11.87 g, 120.0 mmol, 3.00 eq.), and tetrakis(triphenylphosphine) palladium (0) (2.31 g, 2.0 mmol, 0.05 eq.) were added in sequence. The reaction mixture was stirred at 95° C. for 18 hours. The mixture was allowed to cool to r.t. and partitioned between DCM (200 mL) and water (100 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (2×50 mL), dried over MgSO₄, filtered over celite and concentrated in vacuo. The residue was purified by flashmaster (column: 340 g, flow: 90 mL/min, 90 fractions of 45 mL, Heptane to Heptane+40% AcOEt) to yield the desired pinacol boronic ester as a yellow oil.

Listed in Table 45 below are pinacol boronic ester 8 or 11, prepared according to the above-mentioned method, with corresponding bromides 9 or Structure 7 as starting material.

TABLE 45 t_(R) [min] Formula LC-MS MS-data Pinacol boronic ester 8 or 11 MW Method m/z [M + H]⁺ [4-Methoxy-3-(4,4,5,5-tetramethyl- C17H25O5B 0.90 321.2 [1,3,2]dioxaborolan-2-yl)-phenyl]-acetic 320.18 LC-MS 3 acid ethyl ester [4-Fluoro-3-(4,4,5,5-tetramethyl- C16H22O4BF 0.95 309.4 [1,3,2]dioxaborolan-2-yl)-phenyl]-acetic 308.16 LC-MS 3 acid ethyl ester 5-Fluoro-8-(4,4,5,5-tetramethyl- C23H27NO4BF 1.07 412.1 [1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H- 411.20 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester [5-Fluoro-8-(4,4,5,5-tetramethyl- C25H29NO3BF 1.05 422.1 [1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H- 421.22 LC-MS 3 isoquinolin-2-yl]-((1R,2R)-2-phenyl- cyclopropyl)-methanone [4-Isopropoxy-3-(4,4,5,5-tetramethyl- C19H29O6B 0.97 365.2 [1,3,2]dioxaborolan-2-yl)-phenoxy]-acetic 364.21 LC-MS 3 acid ethyl ester [4-Ethoxy-3-(4,4,5,5-tetramethyl- C18H27O5B 0.96 335.3 [1,3,2]dioxaborolan-2-yl)-phenyl]-acetic 334.20 LC-MS 3 acid ethyl ester

General Method for the Synthesis of Esters of Structure 6

A mixture under N₂ of 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (206 mg, 0.5 mmol, 1.00 eq.), (3-bromo-4-isopropoxy-phenyl)-acetic acid ethyl ester (151 mg, 0.5 mmol, 1.00 eq.), tetrakis(triphenylphosphine) palladium (0) (29 mg, 0.025 mmol, 0.05 eq.), and sodium carbonate (212 mg, 2.0 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (5 mL) was stirred at 100° C. for 48 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (50 mL) and water (50 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 50 fractions of 45 mL, Heptane to Heptane+30% AcOEt) to yield the desired compound as a colorless oil.

Listed in Table 46 below are esters of Structure 6, prepared according to the above-mentioned method, with corresponding halogenated compound 9 as starting material.

TABLE 46 t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 6 MW Method [M + H]⁺ 8-(5-Ethoxycarbonylmethyl-2-isopropoxy- C30H32NO5F 1.07 506.3 phenyl)-5-fluoro-3,4-dihydro-1H- 505.23 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester 5-Fluoro-8-(5-methoxycarbonylmethyl-2- C27H26NO4F 1.03 448.3 methyl-phenyl)-3,4-dihydro-1H- 447.19 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 5-Fluoro-8-(5-methoxycarbonylmethyl-2- C27H23NO4F4 1.03 502.3 trifluoromethyl-phenyl)-3,4-dihydro-1H- 501.16 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(2-Chloro-5-methoxycarbonylmethyl- C26H23NO4ClF 1.03 468.3 phenyl)-5-fluoro-3,4-dihydro-1H- 467.13 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2-fluoro- C27H25NO4F2 1.03 466.2 phenyl)-5-fluoro-3,4-dihydro-1H- 465.18 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(4-Chloro-3-ethoxycarbonylmethyl- C27H25NO4ClF 1.07 482.2 phenyl)-5-fluoro-3,4-dihydro-1H- 481.15 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(3-Ethoxycarbonylmethyl-4-fluoro- C27H25NO4F2 1.05 466.3 phenyl)-5-fluoro-3,4-dihydro-1H- 465.18 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(3-Ethoxycarbonylmethyl-4-methoxy- C28H28NO5F 1.05 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(3-Ethoxycarbonylmethyl-5-fluoro- C27H25NO4F2 1.05 466.4 phenyl)-5-fluoro-3,4-dihydro-1H- 465.18 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(3-Ethoxycarbonylmethyl-5-methoxy- C28H28NO5F 1.04 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(3-Ethoxycarbonylmethyl-2-fluoro- C27H25NO4F2 1.01 466.4 phenyl)-5-fluoro-3,4-dihydro-1H- 465.18 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2-methoxy- C28H28NO5F 1.02 478.4 phenyl)-5-fluoro-3,4-dihydro-1H- 477.20 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(3-Chloro-5-ethoxycarbonylmethyl- C27H25NO4ClF 1.06 482.4 phenyl)-5-fluoro-3,4-dihydro-1H- 481.15 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2- C28H28NO6FS 0.97 526.2 methanesulfonyl-phenyl)-5-fluoro-3,4- 525.16 LC-MS 3 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2- C28H25NO5F4 1.07 532.2 trifluoromethoxy-phenyl)-5-fluoro-3,4- 531.17 LC-MS 3 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 8-(2-Ethoxycarbonylmethyl-phenyl)-5- C27H26NO4F 1.03 448.1 fluoro-3,4-dihydro-1H-isoquinoline-2- 447.19 LC-MS 3 carboxylic acid benzyl ester 8-(3-Chloro-4-ethoxycarbonylmethyl- C27H25NO4ClF 1.07 482.0 phenyl)-5-fluoro-3,4-dihydro-1H- 481.15 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(4-Ethoxycarbonylmethyl-phenyl)-5- C27H26NO4F 1.05 448.3 fluoro-3,4-dihydro-1H-isoquinoline-2- 447.19 LC-MS 3 carboxylic acid benzyl ester

General Method for the Synthesis of Ester of Structure 1

To a mixture under N₂ of [5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-((1R,2R)-2-phenyl-cyclopropyl)-methanone (41 mg, 0.1 mmol, 1.00 eq.) and sodium carbonate (41 mg, 0.4 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (3 mL), (3-bromo-4-trifluoromethoxy-phenyl)-acetic acid ethyl ester (35 mg, 0.11 mmol, 1.10 eq.) and tetrakis(triphenylphosphine) palladium (0) (5.6 mg, 5 μmol, 0.05 eq) were added in sequence. The mixture was refluxed for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired ester.

Listed in Table 47 below are esters of Structure 1, prepared according to the above-mentioned method, with corresponding halogenated compound 9 as starting material.

TABLE 47 t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 1 MW Method [M + H]⁺ {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C30H27NO4F4 1.05 542.1 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 541.19 LC-MS 3 isoquinolin-8-yl]-4-trifluoromethoxy- phenyl}-acetic acid ethyl ester {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C32H34NO4F 1.05 516.3 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 515.25 LC-MS 3 isoquinolin-8-yl]-4-isopropoxy-phenyl}- acetic acid ethyl ester {4-Chloro-3-[5-fluoro-2-((1R,2R)-2-phenyl- C28H25NO3ClF 1.02 478.2 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 477.15 LC-MS 3 isoquinolin-8-yl]-phenyl}-acetic acid methyl ester {3-[5-Fluoro-2-((1R,2R)-2-phenyl- C30H30NO5FS 0.95 536.2 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 535.18 LC-MS 3 isoquinolin-8-yl]-4-methanesulfonyl- phenyl}-acetic acid ethyl ester

General Method for the Formation of a Triflate and Subsequent Suzuki Cross-Coupling

Method A: To an ice-cooled solution of 8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (142 mg, 0.50 mmol, 1.00 eq.) in DCM (1 mL), NEt₃ (0.21 mL, 1.50 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (0.13 mL, 0.75 mmol, 1.50 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (50 mL) and washed with sat. aq. NaHCO₃ soln. (2×25 mL). The org. layer was dried over MgSO₄ and concentrated in vacuo. To a mixture under N₂ of the resulting triflate, 2-benzyloxy-5-fluorobenzeneboronic acid (123 mg, 0.50 mmol, 1.00 eq.), and sodium carbonate (212 mg, 2.00 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (2.5 mL), tetrakis(triphenylphosphine) palladium (0) (29 mg, 0.03 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 14 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by CC (SiO₂, Hept/AcOEt 8:2) to give the product as an yellow oil.

Listed in Table 48 below are intermediates, prepared according to the above-mentioned method, with corresponding phenol and boronic acid or boronic ester as starting material.

TABLE 48 t_(R) [min] Formula LC-MS MS-data m/z Intermediates MW Method [M + H]⁺ 8-(2-Benzyloxy-5-fluoro-phenyl)-3,4-dihydro- C30H26NO3F 1.07 468.2 1H-isoquinoline-2-carboxylic acid 467.19 LC-MS 2 benzyl ester 8-(5-Ethoxycarbonylmethyl-2-fluoro- C27H26NO4F 1.02 448.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 447.19 LC-MS 3 carboxylic acid benzyl ester 8-(2-Chloro-5-hydroxy-phenyl)-3,4- C23H20NO3Cl 0.95 394.1 dihydro-1H-isoquinoline-2-carboxylic acid 393.11 LC-MS 3 benzyl ester

Method B: To an ice-cooled solution of (3-hydroxy-4-propyl-phenyl)-acetic acid tert-butyl ester (66 mg, 0.26 mmol, 1.30 eq.) and triethylamine (0.11 mL, 0.78 mmol, 3.90 eq.) in DCM (1 mL), trifluoromethanesulfonic anhydride (68 μL, 0.39 mmol, 1.90 eq.) was added dropwise. The resulting solution was stirred at r.t. for 1 hour. The reaction mixture was concentrated in vacuo. A mixture under N₂ of 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (91 mg, 0.20 mmol, 1.0 eq.), the previous triflate and tetrakis(triphenylphosphine) palladium (0) (12 mg, 0.01 mmol, 0.05 eq.) was dissolved in DME/EtOH/Toluene (9:1:1, 0.7 mL). 2M aq. Na₂CO₃ soln. (0.2 mL) was added and the mixture was stirred at 90° C. for 3 hours. The mixture was filtered over Celite and the filter cake was rinced with EtOH. The filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired product as a brown oil.

Listed in Table 49 below are intermediates, prepared according to the above-mentioned method, with corresponding phenol and boronic acid or boronic ester as starting material.

TABLE 49 t_(R) [min] Formula LC-MS MS-data m/z Intermediates MW Method [M + H]⁺ 8-(5-tert-Butoxycarbonylmethyl-2-propyl- C32H36NO4F 1.13 518.2 phenyl)-5-fluoro-3,4-dihydro-1H- 517.26 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(4-tert-Butoxycarbonylmethyl-2- C32H36NO4F 1.14 518.2 isopropyl-phenyl)-5-fluoro-3,4-dihydro-1H- 517.26 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(4-Ethoxycarbonylmethyl-2,6-dimethoxy- C29H30NO6F 1.02 508.2 phenyl)-5-fluoro-3,4-dihydro-1H- 507.21 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester

General Method for the Synthesis of Esters of Structure 6

A mixture under N₂ of palladium(II)acetate (2.1 mg, 9.4 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (7.9 mg, 0.02 mmol, 0.02 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (525 mg, 1.44 mmol, 1.50 eq.) and potassium phosphate (408 mg, 1.92 mmol, 2.00 eq.) in toluene (1.9 mL) and water (0.2 mL) was stirred at r.t. for 2 min. 8-Chloro-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (355 mg, 0.96 mmol, 1.00 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., diluted with Et₂O (10 mL), filtered through celite, washed with Et₂O, and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 30 fractions of 40 mL, Heptane+5% AcOEt to Heptane+30% AcOEt) to yield the desired product as a pale yellow oil.

Listed in Table 50 below are esters of Structure 6, prepared according to the above-mentioned method, with corresponding compound of Structure 7 as starting material.

TABLE 50 t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 6 MW Method [M + H]⁺ 8-(5-Ethoxycarbonylmethyl-2-methoxy- C29H28NO5F3 1.05 528.4 phenyl)-5-trifluoromethyl-3,4-dihydro-1H- 527.19 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2-methoxy- C29H31NO7S 0.94 538.1 phenyl)-5-methanesulfonyl-3,4-dihydro- 537.18 LC-MS 3 1H-isoquinoline-2-carboxylic acid benzyl ester

General Method for the Synthesis of an Ester of Structure 6

To a mixture under N₂ of [3-bromo-4-(2-methoxy-ethoxy)-phenyl]-acetic acid ethyl ester (159 mg, 0.50 mmol, 1.00 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (243 mg, 0.50 mmol, 1.00 eq.) and sodium carbonate (212 mg, 2.00 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (10 mL), tetrakis(triphenylphosphine) palladium (0) (29 mg, 0.03 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 48 hours. The mixture was allowed to cool to r.t., filtered over celite, and concentrated in vacuo. The residue, redissolved in DMF (3 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired product as an orange oil.

Listed in Table 51 below are esters of Structure 6, prepared according to the above-mentioned method, with corresponding compound 9 as starting material.

TABLE 51 t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 6 MW Method [M + H]⁺ 8-[5-Ethoxycarbonylmethyl-2-(2-methoxy- C30H32NO6F 1.02 522.3 ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H- 521.22 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(2-Ethoxy-5-ethoxycarbonylmethyl- C29H30NO5F 1.05 492.4 phenyl)-5-fluoro-3,4-dihydro-1H- 491.21 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(2-Ethoxy-4-ethoxycarbonylmethyl- C29H30NO5F 1.06 492.4 phenyl)-5-fluoro-3,4-dihydro-1H- 491.21 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-[4-Ethoxycarbonylmethyl-2-(2,2,2- C29H27NO5F4 1.06 545.9 trifluoro-ethoxy)-phenyl]-5-fluoro-3,4- 545.18 LC-MS 3 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

Synthesis of 8-(4-tert-Butoxycarbonylmethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C32H36NO5F, MW=533.26)

A mixture under N₂ of (4-chloro-3-isopropoxy-phenyl)-acetic acid tert-butyl ester (142 mg, 0.50 mmol, 1.00 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (232 mg, 0.50 mmol, 1.00 eq.), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (18 mg, 0.03 mmol, 0.05 eq.) and potassium carbonate (138 mg, 1.00 mmol, 2.00 eq.) in toluene (2.5 mL) and water (0.25 mL) was stirred at 110° C. for 2 days. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to yield the title compound as a pale yellow oil.

LC-MS 3: t_(R)=1.12 min; [M+H]⁺=534.2

Synthesis of 8-(3-Ethoxycarbonylmethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H26NO4F, MW=447.19)

To a mixture under N₂ of 8-bromo-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (73 mg, 0.20 mmol, 1.00 eq.), (3-ethoxycarbonylmethyl)phenylboronic acid, pinacol ester (58 mg, 0.20 mmol, 1.00 eq.) and sodium carbonate (85 mg, 0.80 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (4 mL), tetrakis(triphenylphosphine) palladium (0) (12 mg, 0.01 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours.

The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×5 mL), dried over MgSO₄, and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by CC (SiO₂, eluent: Hept./AcOEt 8:2) to give the desired product as a yellow oil.

LC-MS 3: t_(R)=1.05 min; [M+H]⁺=448.1

Synthesis of 5-(5-Ethoxycarbonylmethyl-2-methoxy-phenyl)-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C28H28NO5F, MW=477.20)

To a mixture under N₂ of 5-bromo-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (529 mg, 1.45 mmol, 1.00 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (659 mg, 1.45 mmol, 1.00 eq.) and sodium carbonate (616 mg, 5.81 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (29 mL), tetrakis(triphenylphosphine) palladium (0) (84 mg, 0.07 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (60 mL) and water (60 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×60 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 40 fractions of 40 mL, Heptane 100% to Heptane+30% AcOEt) to yield the title compound as a yellow oil.

LC-MS 3: t_(R)=1.03 min; [M+H]⁺=478.2

Synthesis of 8-(5-Ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (C25H30NO5F, MW=443.21)

To a mixture under N₂ of 8-bromo-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.24 g, 3.75 mmol, 1.00 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.69 g, 3.75 mmol, 1.00 eq.) and sodium carbonate (1.59 g, 15.00 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (75 mL), tetrakis(triphenylphosphine) palladium (0) (217 mg, 0.19 mmol, 0.05 eq.) was added and the mixture was stirred under reflux at 100° C. for 70 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (150 mL) and water (150 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×75 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 40 mL, Heptane+10% AcOEt to Heptane+25% AcOEt) to yield the desired ester as a pale yellow oil.

LC-MS 3: t_(R)=1.02 min; [M+H]⁺=444.1

Synthesis of [3-(5-Chloro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (C20H22NO3Cl, MW=359.13)

To a mixture under N₂ of 8-bromo-5-chloro-1,2,3,4-tetrahydro-isoquinoline hydrochloride (566 mg, 2.00 mmol, 1 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (901 mg, 2.0 mmol, 1.00 eq) and sodium carbonate (1.06 g, 10.0 mmol, 5.00 eq.) in toluene/MeOH/water 20:4:1 (40 mL), tetrakis(triphenylphosphine) palladium (0) (116 mg, 0.1 mmol, 0.05 eq.) was added and the mixture was stirred under reflux for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (75 mL) and water (75 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, AcOEt+MeOH 10%) to yield the title product as an orange oil.

LC-MS 2: t_(R)=0.69 min; [M+H]⁺=360.1

Synthesis of (±)-8-[5-(1-Ethoxycarbonyl-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C29H30NO5F, MW=491.21)

A mixture under N₂ of palladium(II)acetate (1.2 mg, 5 μmol, 0.02 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.2 mg, 0.01 mmol, 0.04 eq.), (±)-2-(3-bromo-4-methoxy-phenyl)-propionic acid ethyl ester (80 mg, 0.26 mmol, 1 eq.) and potassium phosphate (109 mg, 0.51 mmol, 2 eq.) in toluene (1.9 mL) and water (0.2 mL) was stirred at r.t. during 2 min. 5-Fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (147 mg, 0.26 mmol, 1 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., diluted with Et₂O (10 mL), filtered through celite, washed with Et₂O, and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a colorless oil.

LC-MS 3: t_(R)=1.04 min; [M+H]⁺=492.2

Synthesis of 8-(5-Fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C23H20NO3F, MW=377.14)

To a solution under N₂ of 8-(2-benzyloxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (208 mg, 0.45 mmol, 1.0 eq.) in EtOH (10 mL), palladium on activated carbon (10 wt. %, 21 mg) was added. The flask was evacuated and refilled with H₂. The black suspension was stirred at r.t. under an H₂-atmosphere for 6 hours. The black suspension was filtered through Celite and the filtrate was concentrated in vacuo to give a beige foam. To an-ice cooled suspension of the residue and triethylamine (93 μL, 0.67 mmol, 1.5 eq.) in DCM (10 mL), benzyl chloroformate (67 μL, 0.45 mmol, 1.0 eq.) was added dropwise. Upon completion of the addition, the mixture was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (10 mL). The layers were separated. The aq. phase was extracted with DCM (3×10 mL). The comb. org. phases were dried over Na₂SO₄ and concentrated in vacuo. The residue was dissolved in THF (10 mL) and 1M aq. NaOH (2 mL) was added. The mixture was stirred at r.t. for 64 hours. The org. solvent was removed in vacuo and the aq. layer was acidified with 2N aq. HCl. The aq. layer was extracted with DCM (3×10 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by CC (SiO₂, Hept/AcOEt 7:3) to give the title compound as a white foam.

LC-MS 2: t_(R)=0.90 min; [M+H]⁺=378.1

Synthesis of (±)-5-Fluoro-8-[2-methoxy-4-(1-methoxycarbonyl-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C28H28NO6F, MW=493.19)

A mixture under N₂ of palladium (II) acetate (0.4 mg, 2 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.7 mg, 4 μmol, 0.02 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (95 mg, 0.20 mmol, 1.00 eq.) and potassium phosphate (85 mg, 0.40 mmol, 2.00 eq.) in toluene (0.6 mL) and water (0.035 mL) was stirred at r.t. for 2 min. A solution of (±)-2-(4-Bromo-3-methoxy-phenoxy)-propionic acid methyl ester (58 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 2 days. The mixture was allowed to cool to r.t., filtered through celite and concentrated in vacuo. The crude residue, redissolved in MeCN (1.5 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a colorless oil.

LC-MS 3: t_(R)=1.03 min; [M+H]⁺=494.3

General Method for the Synthesis of Phenols 13

To a mixture under N₂ of 8-bromo-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (146 mg, 0.40 mmol, 1.00 eq.), 5-hydroxy-2-methoxyphenylboronic acid (69 mg, 0.40 mmol, 1.00 eq.) and sodium carbonate (170 mg, 1.60 mmol, 4.00 eq.) in toluene/MeOH/Water 20:4:1 (8 mL), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol, 0.05 eq.) was added and the mixture was stirred under reflux at 100° C. for 48 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (20 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 10 g, flow: 15 mL/min, 30 fractions of 15 mL, Heptane 100% to Heptane+32% AcOEt) to yield the desired phenol as a pale yellow foam.

Listed in Table 52 below are phenols 13, prepared according to the above-mentioned method, with corresponding compound of Structure 7 and the corresponding boronic acid derivative as starting materials.

TABLE 52 t_(R) [min] Formula LC-MS MS-data m/z Phenols 13 MW Method [M + H]⁺ 5-Fluoro-8-(5-hydroxy-2-methoxy- C24H22NO4F 0.94 407.7 phenyl)-3,4-dihydro-1H-isoquinoline-2- 407.15 LC-MS 3 carboxylic acid benzyl ester 5-Fluoro-8-(3-hydroxy-phenyl)-3,4- C23H20NO3F 0.95 377.8 dihydro-1H-isoquinoline-2-carboxylic 377.14 LC-MS 3 acid benzyl ester 8-(2-Chloro-5-hydroxy-phenyl)-5-fluoro- C23H19NO3ClF 0.97 412.0 3,4-dihydro-1H-isoquinoline-2- 411.10 LC-MS 3 carboxylic acid benzyl ester 8-(4-Chloro-3-hydroxy-phenyl)-5-fluoro- C23H19NO3ClF 0.99 411.9 3,4-dihydro-1H-isoquinoline-2- 411.10 LC-MS 3 carboxylic acid benzyl ester 8-(3-Chloro-5-hydroxy-phenyl)-5-fluoro- C20H21NO3ClF 0.99 378.0 3,4-dihydro-1H-isoquinoline-2- 377.12 LC-MS 3 carboxylic acid tert-butyl ester 8-(5-Chloro-2-hydroxy-phenyl)-5-fluoro- C20H21NO3ClF 0.99 378.0 3,4-dihydro-1H-isoquinoline-2- 377.12 LC-MS 3 carboxylic acid tert-butyl ester 8-(3-Chloro-5-hydroxy-phenyl)-5- C21H21NO3ClF3 1.03 No ionization trifluoromethyl-3,4-dihydro-1H- 427.12 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester 5-Chloro-8-(2-chloro-5-hydroxy- C23H19NO3Cl2 0.99 428.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 427.07 LC-MS 3 carboxylic acid benzyl ester 8-(2-Chloro-5-hydroxy-phenyl)-5- C24H22NO4Cl 0.96 424.2 methoxy-3,4-dihydro-1H-isoquinoline- 423.12 LC-MS 3 2-carboxylic acid benzyl ester 8-(2-Chloro-5-hydroxy-phenyl)-5- C24H22NO3Cl 0.97 408.2 methyl-3,4-dihydro-1H-isoquinoline-2- 407.13 LC-MS 3 carboxylic acid benzyl ester 8-(2-Chloro-5-hydroxy-phenyl)-5- C24H19NO3ClF3 1.00 462.2 trifluoromethyl-3,4-dihydro-1H- 461.10 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester

Synthesis of [5-Fluoro-8-(5-hydroxy-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-((1R,2R)-2-phenyl-cyclopropyl)-methanone (C26H24NO3F, MW=417.17)

To a mixture under N₂ of (8-bromo-5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-((1R,2R)-2-phenyl-cyclopropyl)-methanone (289 mg, 0.76 mmol, 1.00 eq.), 5-hydroxy-2-methoxyphenylboronic acid (131 mg, 0.76 mmol, 1.00 eq.) and sodium carbonate (324 mg, 3.05 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (15 mL), tetrakis(triphenylphosphine) palladium (0) (44 mg, 0.04 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 62 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (30 mL) and water (30 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×15 mL), dried over MgSO₄ and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 28 fractions of 40 mL, Heptane+10% AcOEt to Heptane+50% AcOEt) to yield the title product as a colorless oil.

LC-MS 3: t_(R)=0.91 min; [M+H]⁺=417.9

General Method for the Alkylation of a Phenol 13

Ethyl bromoacetate (54 μL, 0.49 mmol, 1.5 eq.) was added to a solution of 8-(3-chloro-5-hydroxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (124 mg, 0.33 mmol, 1.0 eq.) and K₂CO₃ (136 mg, 0.99 mmol, 3.0 eq.) in DMF (1 mL). The mixture was stirred at r.t. for 18 hours. The reaction mixture was partitioned between AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. extracts were washed with water and sat. aq. NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo to give the desired ester as a yellow oil. The product was used without further purification.

Listed in Table 53 below are esters of Structure 6-A, prepared according to the above-mentioned method, with corresponding phenols 13 as starting material.

TABLE 53 t_(R) [min] Formula LC-MS MS-data m/z Esters 6-A MW Method [M + H]⁺ 8-(3-Chloro-5-ethoxycarbonylmethoxy- C24H27NO5ClF 1.07 464.0 phenyl)-5-fluoro-3,4-dihydro-1H- 463.16 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester 8-(5-Chloro-2-ethoxycarbonylmethoxy- C24H27NO5ClF 1.05 464.0 phenyl)-5-fluoro-3,4-dihydro-1H- 463.16 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester 8-(3-Chloro-5-ethoxycarbonylmethoxy- C25H27NO5ClF3 1.10 513.5 phenyl)-5-trifluoromethyl-3,4-dihydro-1H- 513.15 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester

General Method for the Preparation of Intermediates of Structure 2

To an ice-cooled solution of 8-(3-chloro-5-ethoxycarbonylmethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (173 mg, 0.32 mmol, 1 eq.) in DCM (0.6 mL), 4M HCl in dioxane (1.4 mL) was added. The resulting solution was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was coevaporated with EtOH (3×) to give the desired salt as a pale yellow solid. The product was used without further purification.

Listed in Table 54 below are compounds of Structure 2, prepared according to the above-mentioned method, with corresponding Boc-protected esters of Structure 6 as starting material.

TABLE 54 t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 2 MW Method [M + H]⁺ [3-Chloro-5-(5-fluoro-1,2,3,4-tetrahydro- C19H19NO3ClF 0.73 364.0 isoquinolin-8-yl)-phenoxy]-acetic acid 363.10 LC-MS 3 ethyl ester hydrochloride [4-Chloro-2-(5-fluoro-1,2,3,4-tetrahydro- C19H19NO3ClF 0.73 364.0 isoquinolin-8-yl)-phenoxy]-acetic acid 363.10 LC-MS 3 ethyl ester hydrochloride [3-Chloro-5-(5-trifluoromethyl-1,2,3,4- C20H19NO3ClF3 0.78 414.0 tetrahydro-isoquinolin-8-yl)-phenoxy]- 413.10 LC-MS 3 acetic acid ethyl ester hydrochloride [3-(5-Fluoro-1,2,3,4-tetrahydro- C20H22NO3F 0.69 344.3 isoquinolin-8-yl)-4-methoxy-phenyl]-acetic 343.16 LC-MS 3 acid ethyl ester hydrochloride

General Method for the Preparation of Intermediates of Structure 2

Method A: A solution of 8-(4-tert-butoxycarbonylmethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (109 mg, 0.20 mmol, 1 eq.) in THF (4 mL, 0.05 M) was hydrogenated through H-Cube (settings: Cartridge Pd(OH)₂/C, Flow=1 mL/min, Mode Full H₂, r.t.). The solution was set in closed circuit for 18 hours. The solvent was removed in vacuo to give the intermediate of Structure 2 as a pale orange oil. The residue was used without further purification.

Listed in Table 55 below are compounds of Structure 2, prepared according to the above-mentioned method, with corresponding Cbz-protected esters of Structure 6 as starting material.

TABLE 55 t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 2 MW Method [M + H]⁺ [4-(5-Fluoro-1,2,3,4-tetrahydro- C24H30NO3F 0.79 400.2 isoquinolin-8-yl)-3-isopropoxy-phenyl]- 399.22 LC-MS 3 acetic acid tert-butyl ester [4-(5-Fluoro-1,2,3,4-tetrahydro- C21H21NO3F4 0.74 412.1 isoquinolin-8-yl)-3-(2,2,2-trifluoro-ethoxy)- 411.15 LC-MS 3 phenyl]-acetic acid ethyl ester [3-(5-Fluoro-1,2,3,4-tetrahydro- C21H21NO3F4 0.74 412.1 isoquinolin-8-yl)-4-(2,2,2-trifluoro-ethoxy)- 411.15 LC-MS 3 phenyl]-acetic acid ethyl ester

Method B: To a solution under N₂ of 8-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (770 mg, 1.61 mmol, 1 eq.) in AcOEt (60 mL), Pd on activated carbon (10 wt. %, 80 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with AcOEt. The filtrate was concentrated in vacuo to give the desired compound of Structure 2. The product was used without further purification.

Listed in Table 56 below are compounds of Structure 2, prepared according to the above-mentioned method, with corresponding Cbz-protected esters of Structure 6 as starting material.

t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 2 MW Method [M + H]⁺ [4-(5-Fluoro-1,2,3,4-tetrahydro- C20H22NO3F 0.68 344.1 isoquinolin-8-yl)-3-methoxy-phenyl]-acetic 343.16 LC-MS 3 acid ethyl ester [3-Ethoxy-4-(5-fluoro-1,2,3,4-tetrahydro- C21H24NO3F 0.71 358.1 isoquinolin-8-yl)-phenyl]-acetic acid ethyl 357.17 LC-MS 3 ester

Synthesis of [3-(5-Fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-isopropoxy-phenyl]-acetic acid ethyl ester (C22H26NO3F, MW=371.19)

To a solution of 8-(5-ethoxycarbonylmethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.65 g, 3.17 mmol, 1 eq.) in EtOH (15.5 mL) under N₂, palladium on activated carbon (10 wt. %, 165 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 24 hours and further at 50° C. for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, AcOEt to (AcOEt+10% NEt₃) to yield the title compound as a colorless oil.

LC-MS 3: t_(R)=0.74 min; [M+H]⁺=372.1

Synthesis of [3-(8-Fluoro-1,2,3,4-tetrahydro-isoquinolin-5-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (C20H22NO3F, MW=343.16)

To a solution of 5-(5-ethoxycarbonylmethyl-2-methoxy-phenyl)-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (760 mg, 1.39 mmol, 1 eq) in EtOH (7 mL) under N₂, palladium on activated carbon (10 wt. %, 76 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 72 hours and further at 40° C. for 3 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 50 fractions of 45 mL, AcOEt to AcOEt+12% MeOH). The desired product was dissolved in 4M HCl in dioxane (10 mL). The resulting solution was stirred at r.t. for 30 min, then concentrated in vacuo. The salt was dissolved in EtOH and concentrated in vacuo (3 times) to afford the tittle salt as a yellow oil.

LC-MS 3: t_(R)=0.67 min; [M+H]⁺=344.1

Synthesis of [4-Methoxy-3-(5-trifluoromethyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester hydrochloride (C21H22NO3F3, MW=393.16)

To a solution of 8-(5-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (426 mg, 0.79 mmol, 1 eq) in EtOH (4 mL) under N₂, palladium on activated carbon (10 wt. %, 43 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 3 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was dissolved in 4M HCl in dioxane (5 mL). The resulting solution was stirred at r.t. for 18 hours, then concentrated in vacuo. The residue was dissolved in EtOH and concentrated in vacuo (3 times) to afford the tittle salt as a pale yellow solid.

LC-MS 3: t_(R)=0.74 min; [M+H]⁺=394.3

Synthesis of (±)-Ethyl 2-(3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)-4-methoxyphenyl)propanoate (C21H24NO3F, MW=357.17)

To a solution under N₂ of (±)-8-[5-(1-ethoxycarbonyl-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (57 mg, 0.12 mmol, 1 eq.) in EtOH (40 mL), palladium on activated carbon (10 wt. %, 3.2 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at 50° C. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo to afford the title product as a yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.72 min; [M+H]⁺=358.1

Synthesis of ethyl 2-(4-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methoxyphenyl)acetate (C20H22NO3F, MW=343.16)

Step 1: A mixture under N₂ of palladium(II)acetate (13 mg, 0.06 mmol, 0.02 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (48 mg, 0.12 mmol, 0.04 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.20 g, 2.92 mmol, 1.00 eq.) and potassium phosphate (1.24 g, 5.84 mmol, 2.00 eq.) in toluene (8 mL) and water (0.8 mL) was stirred at r.t. during 2 min. (4-Bromo-3-methoxy-phenyl)-acetic acid ethyl ester (797 mg, 2.92 mmol, 1.00 eq) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., diluted with Et₂O (10 mL), filtered through celite, washed with Et₂O and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield 8-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a colorless oil.

LC-MS 3: t_(R)=1.03 min; [M+H]⁺=478.3

Step 2: To a solution under N₂ of 8-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (770 mg, 1.61 mmol, 1 eq.) in AcOEt (60 mL), palladium on activated carbon (10 wt. %, 80 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with AcOEt. The filtrate was concentrated in vacuo to give ethyl 2-(4-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methoxyphenyl)acetate as an yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.68 min; [M+H]⁺=344.1

General Method for the Synthesis of Isoquinolines 14

A mixture under N₂ of palladium(II)acetate (11 mg, 51 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (43 mg, 0.10 mmol, 0.02 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (3.29 g, 7.78 mmol, 1.50 eq.) and potassium phosphate (2.20 g, 10.4 mmol, 2.00 eq.) in toluene (10 mL) and water (1 mL) was stirred at r.t. during 2 min. 8-Chloro-5,6-difluoro-isoquinoline (1.11 g, 5.19 mmol, 1.00 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t, diluted with Et₂O (55 mL), filtered through celite, washed with Et₂O, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+5% AcOEt to Heptane+45% AcOEt) to yield the desired isoquinoline as a yellow oil.

Listed in Table 57 below are isoquinolines 14, prepared according to the above-mentioned method, with corresponding isoquinolines 15 as starting material.

TABLE 57 t_(R) [min] MS-data Formula LC-MS m/z Isoquinolines 14 MW Method [M + H]⁺ [3-(5,6-Difluoro-isoquinolin-8-yl)-4-methoxy- C20H17NO3F2 0.81 358.1 phenyl]-acetic acid ethyl ester 357.12 LC-MS 3 [3-(7-Fluoro-isoquinolin-8-yl)-4-methoxy- C20H18NO3F 0.70 340.1 phenyl]-acetic acid ethyl ester 339.13 LC-MS 3 [3-(6-Fluoro-isoquinolin-8-yl)-4-methoxy- C20H18NO3F 0.72 340.2 phenyl]-acetic acid ethyl ester 339.13 LC-MS 3

Synthesis of [3-(5,7-Difluoro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (C20H17NO3F2, MW=357.12)

To an ice-cooled suspension of 5,7-difluoro-isoquinolin-8-ol (200 mg, 1.10 mmol, 1.00 eq.) in DCM (10 mL), NEt₃ (0.46 mL, 3.31 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (0.29 mL, 1.66 mmol, 1.50 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (20 mL) and washed with sat. aq. NaHCO₃ soln. (2×10 mL). The org. layer was dried over MgSO₄ and concentrated in vacuo. To a mixture under N₂ of the resulting triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (354 mg, 1.10 mmol, 1.00 eq.), and sodium carbonate (468 mg, 4.42 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (10 mL), tetrakis(triphenylphosphine) palladium (0) (64 mg, 0.06 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a brown oil.

LC-MS 3: t_(R)=0.83 min; [M+H]⁺=358.0

General Method for the Catalytic Hydrogenation of Isoquinolines 14

To a solution under N₂ of [3-(7-fluoro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (75 mg, 0.221 mmol, 1 eq) in AcOEt (20 mL), platinum(IV) oxide hydrate (80-82% Pt) (43 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with AcOEt. The filtrate was concentrated in vacuo to give the desired tetrahydroisoquinoline as a yellow oil. The product was used without further purification.

Listed in Table 58 below are tetrahydroisoquinolines 2-A, prepared according to the above-mentioned method, with corresponding isoquinolines 14 as starting material.

TABLE 58 t_(R) [min] Formula LC-MS MS-data m/z Tetrahydroisoquinolines 2-A MW Method [M + H]⁺ [3-(7-Fluoro-1,2,3,4-tetrahydro-isoquinolin- C20H22NO3F 0.68 344.1 8-yl)-4-methoxy-phenyl]-acetic acid ethyl 343.16 LC-MS 3 ester [3-(6-Fluoro-1,2,3,4-tetrahydro-isoquinolin- C20H22NO3F 0.69 344.1 8-yl)-4-methoxy-phenyl]-acetic acid ethyl 343.16 LC-MS 3 ester [3-(5,7-Difluoro-1,2,3,4-tetrahydro- C20H21NO3F2 0.69 362.1 isoquinolin-8-yl)-4-methoxy-phenyl]-acetic 361.15 LC-MS 3 acid ethyl ester [3-(5,6-Difluoro-1,2,3,4-tetrahydro- C20H21NO3F2 0.70 362.1 isoquinolin-8-yl)-4-methoxy-phenyl]-acetic 361.15 LC-MS 3 acid ethyl ester

General Method for the Synthesis of a Nitrophenol Carbamate 5

To a solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (368 mg, 0.96 mmol, 1.0 eq.) in DCM (10 mL) and N-ethyldiisopropylamine (0.41 mL, 2.40 mmol, 2.5 eq), 4-nitrophenyl chloroformate (232 mg, 1.15 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 1 hour. The reaction was quenched with 1M aq. citric acid soln. (10 mL). The layers were separated. The aq. phase was extracted with DCM (3×10 mL). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo to give the title compound as a yellow foam. The product was used without further purification.

Listed in Table 59 below are examples of nitrophenol carbamate 5, prepared according to the above-mentioned method with the corresponding compound of Structure 2 (or the corresponding salt) as starting material.

TABLE 59 t_(R) [min] Formula LC-MS MS-data m/z Nitrophenol carbamate 5 MW Method [M + H]⁺ 8-(5-Ethoxycarbonylmethyl-2-methoxy- C27H25N2O7F 1.02 509.2 phenyl)-5-fluoro-3,4-dihydro-1H- 508.17 LC-MS 3 isoquinoline-2-carboxylic acid 4-nitro-phenyl ester 8-(2-Ethoxy-5-ethoxycarbonylmethyl- C28H27N2O7F 1.05 523.2 phenyl)-5-fluoro-3,4-dihydro-1H- 522.18 LC-MS 3 isoquinoline-2-carboxylic acid 4-nitro-phenyl ester 8-(2-Ethoxy-4-ethoxycarbonylmethyl- C28H27N2O7F 1.05 523.2 phenyl)-5-fluoro-3,4-dihydro-1H- 522.18 LC-MS 3 isoquinoline-2-carboxylic acid 4-nitro-phenyl ester

Synthesis of 1-Bromo-2,3-bis-bromomethyl-4-fluoro-benzene (C8H6Br3F, MW=357.80)

To a solution of 6-bromo-3-fluoro-o-xylene (2.03 g, 10.00 mmol, 1.00 eq.) in trifluoromethylbenzene (40 mL), N-bromsuccinimide (3.56 g, 20.00 mmol, 2.00 eq.) and benzoyl peroxide (49 mg, 0.15 mmol, 0.015 eq.) were added in sequence. The reaction mixture was heated at 85° C. for 18 hours. The mixture was allowed to cool to r.t., filtered, and the solid rinsed with heptane. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+10% AcOEt) to yield the desired compound as a colorless oil

LC-MS 3: t_(R)=0.94 min; [M+H]⁺=no ionization

Synthesis of [3-(2-Benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (C26H26NO3F, MW=419.19)

To a mixture of 1-bromo-2,3-bis-bromomethyl-4-fluoro-benzene (3.06 g, 8.48 mmol, 1.0 eq.) and K₂CO₃ (2.58 g, 18.70 mmol, 2.2 eq.) in toluene (350 mL), benzylamine (0.94 mL, 8.48 mmol, 1.0 eq.) was added. The mixture was refluxed for 18 hours. The reaction mixture was allowed to cool to r.t. and was concentrated in vacuo. The residue was poured in water (150 mL). The mixture was extracted with DCM (2×100 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was partially purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+10% AcOEt).

To a solution under N₂ of the residue (306 mg, 1.00 mmol, 1.00 eq.) and sodium carbonate (424 mg, 4.00 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (10 mL), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (320 mg, 1.00 mmol, 1.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (58 mg, 0.05 mmol, 0.05 eq.) were added in sequence. The mixture was refluxed for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.

LC-MS 3: t_(R)=0.79 min; [M+H]⁺=420.3

Synthesis of [3-(7-Fluoro-2,3-dihydro-1H-isoindol-4-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (C19H20NO3F, MW=329.14)

To a solution under N₂ of [3-(2-benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (246 mg, 0.59 mmol, 1 eq.) in ethanol (40 mL), palladium on activated carbon (20 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo to give the desired product. The product was used without further purification.

LC-MS 2: t_(R)=0.59 min; [M+H]⁺=330.3

Synthesis of 2,2,2-Trifluoro-1-(6-fluoro-9-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone (C13H13NO2F4, MW=291.09)

Step 1: To a solution of 2-(2-fluoro-5-methoxy-phenyl)-ethylamine (4.30 g, 25.4 mmol, 1.0 eq.) in MeOH (100 mL), glyoxal dimethyl acetal (60% aqueous solution, 5.73 g, 33.0 mmol, 1.3 eq.) was added. The resulting yellow solution was stirred at r.t. for 18 hours. The yellow solution was cooled to 0° C. and sodium borohydride (1.44 g, 38.1 mmol, 1.5 eq.) was added portionwise. The cooling bath was removed and the yellow solution was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and DCM (100 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with water (1×150 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo to give N-(2-fluoro-5-methoxyphenethyl)-2,2-dimethoxyethanamine. The product was used without further purification.

LC-MS 3: t_(R)=0.54 min; [M+H]⁺=258.1

Step 2: N-(2-Fluoro-5-methoxyphenethyl)-2,2-dimethoxyethanamine (3.0 g, 11.7 mmol, 1.0 eq.) was added dropwise to trifluoacetic anhydride (5.2 mL, 37.3 mmol, 3.2 eq.) at −15° C. The reaction mixture was allowed to warm to r.t. and stirred for 25 min. Then, trifluoroacetic acid (9.2 mL, 120.0 mmol, 10.3 eq.) was added and the resulting solution was heated to 40° C. for 18 hours. The reaction mixture was poured in cold water (100 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. To a solution under N₂ of the residue in AcOEt/EtOH 1:1 (60 mL), palladium on activated carbon (10 wt. %, 400 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield the title compound as a white solid.

LC-MS 3: t_(R)=0.90 min; [M+H]⁺=292.2

Synthesis of 9-Fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol (C10H12NOF, MW=181.09)

To a solution of 2,2,2-trifluoro-1-(6-fluoro-9-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone (1.22 g, 4.19 mmol, 1 eq.) in DCM (50 mL), 1M boron tribromide solution in dichloromethane (8.38 mL) was added. The mixture was stirred at r.t. for 2 hours. The reaction was carefully quenched with 2N aq. NaOH soln. (50 mL) and stirred at r.t. for 30 min. The reaction mixture was washed with DCM (2×50 mL). The aq. layer was concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, basic conditions) and concentrated in vacuo to give the desired product.

LC-MS 3: t_(R)=0.41 min; [M+H]⁺=182.4

Synthesis of 6-Fluoro-9-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester (C18H18NO3F, MW=315.13)

To an ice-cooled solution of 9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol (550 mg, 3.04 mmol, 1.0 eq.) and DIPEA (1.56 mL, 9.11 mmol, 3.0 eq.) in a mixture of DMF/DCM 1:2 (30 mL), benzyl chloroformate (0.50 mL, 3.34 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. Then 1M aq. NaOH soln. (10 mL) was added ant the reaction mixture was stirred at r.t. for 1 hour. The mixture was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a brown solid.

LC-MS 3: t_(R)=0.86 min; [M+H]⁺=316.3

Synthesis of 6-(5-Ethoxycarbonylmethyl-2-methoxy-phenyl)-9-fluoro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester (C29H30NO5F, MW=491.21)

To an ice-cooled suspension of 6-fluoro-9-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester (170 mg, 0.54 mmol, 1.00 eq) in DCM (10 mL), NEt₃ (0.23 mL, 1.62 mmol, 3.00 eq) and trifluoromethanesulfonic anhydride (0.14 mL, 0.81 mmol, 1.50 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (20 mL) and washed with sat. aq. NaHCO₃ soln. (2×10 mL). The org. layer was dried over MgSO₄ and concentrated in vacuo. To a mixture under N₂ of the resulting triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (173 mg, 0.54 mmol, 1.00 eq.), and sodium carbonate (229 mg, 2.16 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (10 mL), tetrakis(triphenylphosphine) palladium (0) (31 mg, 0.03 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 17 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a brown oil.

LC-MS 3: t_(R)=1.04 min; [M+H]⁺=492.4

Synthesis of [3-(9-Fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yl)-4-methoxy-phenyl]-acetic acid ethyl ester hydrochloride (C21H24NO3F, MW=357.17)

To a solution under N₂ of 6-(5-carboxymethyl-2-methoxy-phenyl)-9-fluoro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester (80 mg, 0.17 mmol, 1 eq.) in 1.25M hydrogen chloride in ethanol (15 ml), Pd on activated carbon (10 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo to give the desired salt as a colorless oil. The product was used without further purification.

LC-MS 3: t_(R)=0.70 min; [M+H]⁺=358.3

General Method for the Synthesis of Cyclopropanecarboxylic Acid Derivatives (±)-46

Step 1: A solution of 2-chlorocinnamic acid (1.84 g, 10.0 mmol, 1.0 eq.) and N,O-dimethylhydroxylamine hydrochloride (995 mg, 10.0 mmol, 1.0 eq.) in DMF (60 mL) was treated with 4-(dimethylamino)pyridine (4.89 g, 40.0 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.88 g, 15.0 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 62 hours. The reaction mixture was diluted with AcOEt (1 L). The diluted solution was washed with 1N aq. HCl soln. (3×400 mL), sat. aq. NaHCO₃ soln. (3×400 mL), sat. aq. NaCl soln. (1×400 mL), dried over MgSO₄, and concentrated in vacuo to give the desired amide as a pale yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.80 min; [M+H]⁺=226.2

Step 2: To a solution under N₂ of trimethylsulfoxonium (2.20 g, 10.0 mmol, 2.0 eq.) in DMSO (10 mL) maintained at r.t. with a water bath, sodium hydride (60% dispersion in mineral oil, 400 mg, 10.0 mmol, 2.0 eq.) was added portionwise over 10 min. The resulting mixture was stirred at r.t. for 1 hour. A solution of (E)-3-(2-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (1.14 g g, 5.0 mmol, 1.0 eq.) in DMSO (5 mL) was added and the reaction mixture was stirred at r.t. for 19 hours. The reaction mixture was poured in sat. aq. NH₄Cl soln. (50 mL) and extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by CC (SiO₂, Hept/AcOEt) to give the desired cyclopropyl as a colorless oil.

LC-MS 2: t_(R)=0.75 min; [M+H]⁺=240.2

Step 3: To a solution of (±)-(trans)-2-(2-chloro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (1.00 g, 4.20 mmol, 1.0 eq.) in Et₂O (30 mL), tert-butoxide (2.54 g, 22.66 mmol, 5.4 eq.) and H₂O (0.15 mL) were added. The mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in H₂O and the solution was carefully acidified with conc. HCl. The mixture was extracted with DCM (3×20 mL). The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo to give the desired acid as a colorless oil that solidifies upon standing. The residue was used without further purification.

Listed in Table 60 below are cyclopropyl acids (±)-46, prepared according to the above-mentioned method, with the corresponding α,β-unsaturated acid 43 as starting material.

TABLE 60 t_(R) [min] Formula LC-MS MS-data m/z Intermediates (±)-46 MW Method [M + H]⁺ (±)-(trans)-2-(2-Chloro-phenyl)- C10H9O2Cl 0.67 No cyclopropanecarboxylic acid 196.03 LC-MS 2 ionization (±)-(trans)-2-(2-Fluoro-phenyl)- C10H9O2F 0.71 No cyclopropanecarboxylic acid 180.06 LC-MS 3 ionization (±)-(trans)-2-o-Tolyl-cyclopropanecarboxylic C11H12O2 0.73 No acid 176.08 LC-MS 3 ionization (±)-(trans)-2-(4-Chloro-phenyl)- C10H9O2Cl 0.76 No cyclopropanecarboxylic acid 196.03 LC-MS 3 ionization (±)-(trans)-2-(4-Fluoro-phenyl)- C10H9O2F 0.63 No cyclopropanecarboxylic acid 180.06 LC-MS 2 ionization (±)-(trans)-2-(3-Chloro-phenyl)- C10H9O2Cl 0.76 No cyclopropanecarboxylic acid 196.03 LC-MS 3 ionization (±)-(trans)-2-(3-Fluoro-phenyl)- C10H9O2F 0.71 No cyclopropanecarboxylic acid 180.06 LC-MS 3 ionization (±)-(trans)-2-(2,4-Dichloro-phenyl)- C10H8O2Cl2 0.80 No cyclopropanecarboxylic acid 229.99 LC-MS 3 ionization (±)-(trans)-2-(2-Trifluoromethyl-phenyl)- C11H9O2F3 0.78 No cyclopropanecarboxylic acid 230.06 LC-MS 3 ionization (±)-(trans)-2-(4-Methoxy-phenyl)- C11H12O3 0.61 No cyclopropanecarboxylic acid 192.08 LC-MS 2 ionization

Synthesis of (±)-(trans)-2-Pyridin-2-yl-cyclopropanecarboxylic acid (C9H9NO2, MW=163.06)

Step 1: To a suspension of (E)-3-(pyridin-2-yl)acrylic acid (1.49 g, 10 mmol, 1 eq.) and N,O-dimethylhydroxylamine hydrochloride (975 mg, 10 mmol, 1 eq.) in DMF (20 mL), 4-dimethylaminopyridine (4.89 mg, 40 mmol, 4 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (2.30 g, 12 mmol, 1.2 eq.) were added. The resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt (300 mL). The diluted solution was washed with sat. aq. NaHCO₃ soln. (2×150 mL), sat. aq. NaCl soln. (1×150 mL), dried over MgSO₄, and concentrated in vacuo. The resulting product was used without further purification.

LC-MS 3: t_(R)=0.45 min; 193.4

Step 2: To a solution under N₂ of trimethylsulfoxonium iodide (3.89 g, 17.7 mmol, 2 eq.) in DMSO (10 mL) cooled at r.t. with a water bath, sodium hydride 60% dispersion in mineral oil (707 mg, 17.7 mmol, 2 eq.) was added portionwise over 10 min. The resulting mixture was stirred at r.t. for 1 hour. A solution of (E)-N-methoxy-N-methyl-3-(pyridin-2-yl)acrylamide (1.70 g, 8.8 mmol, 1 eq.) in DMSO (5 mL) was added and the reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in sat. aq. NH₄Cl soln. (50 mL) and extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+20% AcOEt to Heptane+80% AcOEt) to yield (±)-(trans)-2-pyridin-2-yl-cyclopropanecarboxylic acid methoxy-methyl-amide as an yellow oil.

LC-MS 3: t_(R)=0.40 min; 207.4

Step 3: To a solution of (±)-(trans)-2-pyridin-2-yl-cyclopropanecarboxylic acid methoxy-methyl-amide (950 mg, 4.61 mmol, 1 eq) in Et₂O (30 mL), potasssium tert-butoxide (569 mg, 5.07 mmol, 1.1 eq) and H₂O (0.4 mL) were added. The mixture was stirred at r.t. for 18 hours. Potasssium tert-butoxide (1.86 g, 16.6 mmol, 3.6 eq.) was added again. The mixture was stirred at r.t. for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (5 mL) and formic acid (3 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the title compound as a white solid.

LC-MS 3: t_(R)=0.27 min; 164.2

General Method for the Synthesis of Cyclopropanecarboxylic Acid Derivatives (R,R)-47

Step 1: A mixture of AD-mix-alpha (7.0 g) in tBuOH (23 mL) and water (23 mL) was stirred at r.t. during 15 min. The mixture was then cooled down to 0° C. and 4-chlorostyrene (0.64 mL, 5.0 mmol, 1.0 eq.) was added. The resulting heterogeneous slurry was stirred vigorously at 0° C. for 3 hours. Sodium sulfite (7.5 g, 59.5 mmol, 11.9 eq.) was added and the reaction mixture was allowed to warm to r.t. and stirred at that temperature for 1 hour. DCM (45 mL) was added and the layers were separated. The aq. phase was extracted with DCM (3×20 mL). The combined org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in DCM (12 mL). Trimethyl orthoacetate (0.85 ml, 6.5 mmol, 1.3 eq.) was added and the mixture was cooled down to 0° C. Chlorotrimethylsilane (0.83 mL, 6.5 mmol, 1.3 eq.) was added dropwise and the reaction mixture was stirred for 1.5 hour. The solvent was removed in vacuo and the residue was dissolved in MeOH, treated with K₂CO₃ (0.86 g) and stirred vigorously at r.t. for 18 hours. The suspension was filtered and the filter cake was washed with DCM. The filtrate was concentrated in vacuo. The resulting residue was dissolved in DCM and water was added. The layers were separated and the aq. phase was extracted once with DCM. The combined org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 28 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield (S)-2-(4-chloro-phenyl)-oxirane as a colorless oil.

LC-MS 3: t_(R)=0.79 min; no ionization

Step 2: To a solution of triethyl phosphonoacetate (1.1 mL, 5.4 mmol, 2.0 eq.) in DME (11 mL) at r.t., 2.5M n-butyllithium solution in hexanes (2.2 mL, 23.9 mmol, 8.9 eq.) was added dropwise over 5 min (the internal temperature should remain under 30° C.). After 15 min a solution of (S)-2-(4-chloro-phenyl)-oxirane (560 mg, 2.7 mmol, 1.0 eq.) in DME (1 mL) was added in one portion. After 15 min the reaction mixture was heated up to 130° C. and stirred at that temperature for 18 hours. The mixture was allowed to cool to r.t. and sat. aq. NH₄Cl soln. was added (25 mL). The mixture was extracted with Et₂O (3×50 mL). The combined org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 28 fractions of 40 mL, Heptane 100% to Heptane+10% AcOEt) to give (1R,2R)-2-(4-chloro-phenyl)-cyclopropanecarboxylic acid ethyl ester as a colorless oil.

LC-MS 3: t_(R)=0.92 min; no ionization

Step 3: To a solution of (1R,2R)-2-(4-chloro-phenyl)-cyclopropanecarboxylic acid ethyl ester (470 mg, 2.1 mmol, 1 eq.) in THF (6.3 mL) and EtOH (1.7 mL), 1M aq. NaOH soln. (3 mL) was added. The solution was stirred at r.t. for 18 hours. The organic solvents were removed in vacuo. The residue was diluted with water and washed with AcOEt. The aq. phase was acidified with 2N aq. HCl soln. The mixture was extracted with DCM (3×). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo to give the desired acid as a white-off solid. The product was used without further purification.

Listed in Table 61 below are cyclopropyl acids (R,R)-47, prepared according to the above-mentioned method, with the corresponding styrene 48 as starting material.

TABLE 61 t_(R) [min] MS-data Formula LC-MS m/z Intermediates (R,R)-47 MW Method [M + H]⁺ (1R,2R)-2-(4-Chloro-phenyl)- C10H9O2Cl 0.76 No cyclopropanecarboxylic acid 196.03 LC-MS 3 ionization (1R,2R)-2-Phenyl-cyclopropane- C10H10O2 0.69 No carboxylic acid 162.07 LC-MS 3 ionization (1R,2R)-2-(2-Fluoro-phenyl)- C10H9O2F 0.71 No cyclopropanecarboxylic acid 180.06 LC-MS 3 ionization (1R,2R)-2-(3-Fluoro-phenyl)- C10H9O2F 0.71 No cyclopropanecarboxylic acid 180.06 LC-MS 3 ionization

Synthesis of (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid (C10H10O2, MW=162.07)

Step 1: To a solution of triethyl phosphonoacetate (0.67 mL, 3.29 mmol, 2.0 eq.) in DME (6.6 mL) at r.t. was added 2.5M n-butyllithium solution in hexanes (1.35 mL, 14.6 mmol, 8.9 eq.) dropwise over 5 min (the internal temperature should remain under 30° C.). After 15 min (1R,2R)-(+)-styrenoxide (0.19 mL, 1.65 mmol, 1.0 eq.) was added in one portion. After 15 min the reaction mixture was heated up to 130° C. and stirred at that temperature for 18 hours. The mixture was allowed to cool to r.t. and sat. aq. NH₄Cl soln was added (15 mL). The mixture was extracted with Et₂O (3×30 mL). The combined org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (1S,2S)-2-phenyl-cyclopropanecarboxylic acid ethyl ester as a colorless liquid.

LC-MS 3: t_(R)=0.87 min; no ionization

Step 2: To a solution of (1S,2S)-2-phenyl-cyclopropanecarboxylic acid ethyl ester (42 mg, 0.22 mmol, 1.0 eq.) in THF (0.68 mL) and EtOH (0.18 mL), 1M aq. NaOH (0.32 ml) was added. The solution was stirred at r.t. for 18 hours. The organic solvents were removed in vacuo. The residue was diluted with water and washed with AcOEt. The aq. phase was acidified with 2N aq. HCl soln. The mixture was extracted with DCM (3×). The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo to give the title compound as a colorless oil. The product was used without further purification.

LC-MS 3: t_(R)=0.69 min; no ionization

General Synthesis of Carboxylic Acid (±)-55

Step 1: To a suspension of sodium hydride 60% dispersion in mineral oil (880 mg, 22 mmol, 2.2 eq.) in THF (30 mL) at 0° C., triethyl phosphonoacetate (4.4 mL, 22 mmol, 2.2 eq.) was added dropwise. The mixture was stirred at 0° C. for 15 min. 4-Chromanone (1.53 g, 10 mmol, 1.0 eq.) was added portionwise. The mixture was slowly warmed up to r.t. and stirred at r.t. for 18 hours (the ice bath was let expire). The reaction mixture was diluted with water (150 mL) and extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln (1×50 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+AcOEt 20%) to yield chroman-(4E)-ylidene-acetic acid ethyl ester as a colorless oil (LC-MS 3: t_(R)=0.90 min; 219.2) and chroman-(4Z)-ylidene-acetic acid ethyl ester (LC-MS 3: t_(R)=0.86 min; 219.3) as a colorless oil (E/Z ratio ca. 3:1).

Step 2: To a solution of chroman-(4E)-ylidene-acetic acid ethyl ester and chroman-(4Z)-ylidene-acetic acid ethyl ester (1.68 g, 7.47 mmol, 1 eq.) in EtOH (91 mL) under N₂, palladium on activated carbon (10 wt. %, 168 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at 45° C. under an H₂-atmosphere for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo to give (±)-chroman-4-yl-acetic acid ethyl ester as a grey oil. The product was used without further purification.

LC-MS 3: t_(R)=0.86 min; 221.3

Step 3: To a solution of (±)-chroman-4-yl-acetic acid ethyl ester (1.74 g, 7.83 mmol, 1 eq.) in THF (24 mL) and EtOH (6.5 mL), 1M aq. NaOH (11.3 mL) was added. The solution was stirred at r.t. for 18 hours. The organic solvents were removed in vacuo. The resulting aq. phase was acidified with 6N aq. HCl soln. The resulting suspension was kept at 4° C. for 4 hours. The resulting suspension was filtered. The solids were rinsed with water and dried under h.v. to give the desired acid as a grey solid. The product was used without further purification.

Listed in Table 62 below are carboxylic acids (±)-55, prepared according to the above-mentioned method, with the corresponding carbonyl derivative 56 as starting material.

TABLE 62 t_(R) [min] Formula LC-MS MS-data m/z Carboxylic acid (±)-55 MW Method [M + H]⁺ (±)-Chroman-4-yl-acetic acid C11H12O3 0.68 No 192.08 LC-MS 3 ionization (±)-(1,2,3,4-Tetrahydro-naphthalen-1-yl)-acetic C12H14O2 0.77 No acid 190.10 LC-MS 3 ionization (±)-Isochroman-4-yl-acetic acid C11H12O3 0.63 193.2 192.08 LC-MS 3 (±)-(8-Fluoro-chroman-4-yl)-acetic acid C11H11O3F 0.70 No 210.07 LC-MS 3 ionization (±)-(6-Fluoro-chroman-4-yl)-acetic acid C11H11O3F 0.71 No 210.07 LC-MS 3 ionization (±)-(7-Fluoro-chroman-4-yl)-acetic acid C11H11O3F 0.72 No 210.07 LC-MS 3 ionization (±)-(2,2-Dimethyl-chroman-4-yl)-acetic acid C13H16O3 0.76 No 220.11 LC-MS 3 ionization (±)-Indan-1-yl-acetic acid C11H12O2 0.73 No 176.08 LC-MS 3 ionization

Synthesis of (±)-Isochroman-1-yl-acetic acid (C11H12O3, 192.08)

Step 1: To an ice-cooled solution of phenethyl alcohol (1.21 mL, 10 mmol, 1.0 eq.) and ethyl 3,3-diethoxy-propionate (2.59 mL, 12 mmol, 1.2 eq) in DCM (5 mL), 1N titantetrachloride solution in DCM (22 mL, 22 mmol, 2.2 eq) was added dropwise. The mixture was stirred at 0° C. for 1 hour and further at r.t. for 3 hours. The mixture was poured onto ice and 2N aq. HCl soln. (30 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane/AcOEt 85:15) to yield (±)-isochroman-1-yl-acetic acid ethyl ester as a colorless oil.

LC-MS 3: t_(R)=0.81 min; 221.2

Step 2: To a solution of (±)-isochroman-1-yl-acetic acid ethyl ester (1.90 g, 8.63 mmol, 1 eq.) in THF (40 mL) and MeOH (10 mL), 1M aq. NaOH soln. (17.3 mL, 17.3 mmol, 2 eq.) was added. The pale yellow solution was stirred at r.t. for 2 hours, then the organic solvents were removed in vacuo. The aq. layer was washed with AcOEt (1×10 mL). The aq. layer was acidified with 1N aq. HCl (pH=1). The resulting emulsion was extracted with DCM (3×25 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo to give the title compound as a colorless oil that solidifies upon standing. The product was used without further purification.

LC-MS 3: t_(R)=0.63 min; no ionization

General Synthesis of Pyridinecarboxylic Acid (±)-52

Step 1: To a suspension of sodium hydride 60% dispersion in mineral oil (480 mg, 12 mmol, 1.2 eq.) in THF (20 mL) at 0° C., dimethyl(benzyloxycarbonyl)methyl phosphonate (2.14 ml, 10 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at 0° C. for 15 min. 2-Acetyl pyridine (1.14 mL, 10 mmol, 1.0 eq.) was added dropwise. The mixture was slowly warmed up to r.t. and stirred at r.t. for 18 hours (the ice bath was let expire). The reaction mixture was quenched with sat. aq. NaHCO₃ soln. (50 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln., dried over MgSO₄, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane 100% to Heptane+40% AcOEt) to yield (E)-3-pyridin-2-yl-but-2-enoic acid benzyl ester as a white solid (LC-MS 3: t_(R)=0.84 min; 254.3) and (Z)-3-pyridin-2-yl-but-2-enoic acid benzyl ester (LC-MS 3: t_(R)=0.63 min; 254.3) as a colorless oil (E/Z ratio ca. 55:13).

Step 2: To a solution under N₂ of (E)-3-pyridin-2-yl-but-2-enoic acid benzyl ester (1.40 g, 5.53 mmol, 1.00 eq.) and (Z)-3-pyridin-2-yl-but-2-enoic acid benzyl ester (320 mg, 1.26 mmol, 0.23 eq.) in THF (50 mL), palladium on activated carbon (10 wt. %, 200 mg) was added. The flask was evacuated and refilled with H₂ (3×). The black suspension was stirred at 50° C. under an H₂-atmosphere for 16 hours. The black suspension was filtered through Celite. The Celite was rinsed with THF and the filtrate was concentrated in vacuo. The residue was dissolved in water (3 mL), MeCN (1 mL) and formic acid (0.5 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 63 below are pyridinecarboxylic acids (±)-52, prepared according to the above-mentioned method, with the corresponding carbonyl derivative 53 as starting material.

TABLE 63 t_(R) [min] MS-data Formula LC-MS m/z Pyridinecarboxylic acid (±)-52 MW Method [M + H]⁺ (±)-3-Pyridin-2-yl-butyric acid C9H11NO2 0.27 166.2 165.08 LC-MS 3 (±)-3-(6-Methoxy-pyridin-2-yl)-butyric acid C10H13NO3 0.53 196.2 195.09 LC-MS 3 (±)-3-(3-Fluoro-pyridin-2-yl)-butyric acid C9H10NO2F 0.51 184.3 183.07 LC-MS 3 (±)-3-(6-Methyl-pyridin-2-yl)-butyric acid C10H13NO2 0.33 180.3 179.10 LC-MS 3 (±)-3-Cyclopropyl-3-pyridin-2-yl-propionic acid C11H13NO2 0.38 192.3 191.10 LC-MS 3 3-(3-Methoxy-pyridin-2-yl)-propionic acid C9H11NO3 0.35 182.4 181.07 LC-MS 3 (±)-3-Pyridin-2-yl-pentanoic acid C10H13NO2 0.34 180.3 179.10 LC-MS 3 (±)-2-(2,2-Dimethyl-3,4-dihydro-2H- C12H15NO3 0.43 222.3 pyrano[2,3-b]pyridin-4-yl)acetic acid 221.11 LC-MS 3 (±)-2-(5,6,7,8-tetrahydroquinolin-8-yl)acetic C11H13NO2 0.39 192.3 acid 191.10 LC-MS 3

Synthesis of (±)-2-Methyl-3-pyridin-2-yl-propionic acid (C9H11NO2, MW=165.08)

Step 1: To a solution of 2-pyridinecarboxaldehyde (0.96 mL, 10 mmol, 1.0 eq.) in toluene (17 mL) was added a solution of (carbethoxyethylidene)triphenylphosphorane (6.50 g, 16.1 mmol, 1.6 eq.) in toluene (24 mL). The resulting mixture was stirred at 80° C. for 18 hours. The solvent was removed in vacuo. The residue was suspended in a minimum amount of water and DCM was added. The product was extracted with 5% HCl soln. The aq. phase was cooled down to 0° C. and was basified with solid K₂CO₃. The product was then extracted with DCM (2×) and the comb. org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, Heptane 100% to Heptane+25% AcOEt). To a solution of the resulting α,β-unsaturated ester in THF (21 mL) under N₂, palladium on activated carbon (10 wt. %, 33 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at 45° C. under an H₂-atmosphere for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with THF. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+AcOEt 30%) to yield (±)-2-methyl-3-pyridin-2-yl-propionic acid ethyl ester as a colorless oil.

LC-MS 3: t_(R)=0.44 min; 194.3

Step 2: To a solution of (±)-2-methyl-3-pyridin-2-yl-propionic acid ethyl ester (250 mg, 1.29 mmol, 1.0 eq.) in dioxane (8 mL), lithium hydroxide monohydrate (67 mg, 1.55 mmol, 1.2 eq.) in water (5 mL) was added in portions keeping the temperature below 30° C. The resulting solution was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo The residue was dissolved in water (3 mL), MeCN (1 mL) and formic acid (0.5 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the title compound as a white solid.

LC-MS 3: t_(R)=0.27 min; 166.2

General Method for the Synthesis of Carbonate 3

To a solution of 4-fluorobenzyl alcohol (631 mg, 5.0 mmol, 1.0 eq.) and DMAP (305 mg, 2.5 mmol, 0.5 eq.) in MeCN/DCM 1:1 (15 mL) N′,N′-disuccinimidyl carbonate (1.28 g, 5.0 mmol, 1.0 eq.) was added. The mixture was stirred at r.t. for 18 hours. The mixture was washed with H₂O (1×15 mL), sat. aq. NaCl soln. (1×15 mL), dried over MgSO₄, filtered and concentrated in vacuo. The residue was recrystallized from iPrOH.

Listed in Table 64 below are carbonates 3, prepared according to the above-mentioned method, with corresponding benzyl alcohols 4 as starting materials.

TABLE 64 t_(R) [min] MS-data Formula LC-MS m/z Carbonates 3 MW Method [M + H]⁺ Carbonic acid 2,5-dioxo- C12H10NO5F 0.69 No pyrrolidin-1-yl ester 4-fluoro- benzyl ester 267.05 LC-MS 2 ionization Carbonic acid 2,5-dioxo- C12H10NO5F 0.78 No pyrrolidin-1-yl ester 3-fluoro- benzyl ester 267.05 LC-MS 3 ionization Carbonic acid 2,5-dioxo- C12H10NO5F 0.78 No pyrrolidin-1-yl ester 2-fluoro- benzyl ester 267.05 LC-MS 3 ionization

General Method for the Carbamate Formation to Give an Intermediate of Structure 1

To an ice-cooled solution of [3-(5,6-difluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (101 mg, 0.20 mmol, 1.0 eq.) and triethylamine (84 μL, 0.60 mmol, 3.0 eq.) in DCM (5.5 mL), benzyl chloroformate (33 μL, 0.22 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (5.5 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters Xbridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired ester as a colorless oil.

Listed in Table 65 below are intermediates of Structure 1, prepared according to the above-mentioned method, with the corresponding intermediate of Structure 2 as starting material.

TABLE 65 MS-data Formula t_(R) [min] m/z Intermediates of Structure 1 MW LC-MS Method [M + H]⁺ 8-(5-Ethoxycarbonylmethyl-2-methoxy- C28H27NO5F2 1.03 496.2 phenyl)-5,6-difluoro-3,4-dihydro-1H- 495.19 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2-methoxy- C28H28NO5F 1.02 478.3 phenyl)-6-fluoro-3,4-dihydro-1H- 477.20 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2-methoxy- C28H28NO5F 1.01 478.3 phenyl)-7-fluoro-3,4-dihydro-1H- 477.20 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester 4-(5-Ethoxycarbonylmethyl-2-methoxy- C27H26NO5F 1.02 464.4 phenyl)-7-fluoro-1,3-dihydro-isoindole-2- 463.18 LC-MS 3 carboxylic acid benzyl ester 8-(5-Ethoxycarbonylmethyl-2-methoxy- C28H27NO5F2 1.02 496.2 phenyl)-5,7-difluoro-3,4-dihydro-1H- 495.19 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester

Synthesis of 8-(2-Ethoxy-4-ethoxycarbonylmethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester (C29H29NO5F2, MW=509.20)

To a solution of [3-ethoxy-4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (1.49 g, 4.2 mmol, 1.00 eq.) and N-ethyldiisopropylamine (3.56 mL, 20.8 mmol, 5.00 eq.) in DCM (50 mL), carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-fluoro-benzyl ester (1.17 g, 4.4 mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 18 hours. The solution was diluted with sat. aq. NaHCO₃ soln. (100 mL). The layers were separated. The aq. phase was extracted with DCM (2×). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 100 fractions of 45 mL, Heptane 100% to Heptane+40% AcOEt) to yield the title compound as a colorless oil.

LC-MS 3: t_(R)=1.06 min; 510.2

General Method for the Amide Coupling to Give an Intermediate of Structure 1

Method A: To a solution of (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (30 mg, 0.19 mmol, 1.2 eq.) in DMF (1 mL), DIPEA (79 μL, 0.46 mmol, 3.0 eq.) and TBTU (60 mg, 0.19 mmol, 1.2 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 minutes. Then [3-(6-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (53 mg, 0.15 mmol, 1.0 eq.) in DMF (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired amide as a yellow oil.

Listed in Table 66 below are intermediates of Structure 1, prepared according to the above-mentioned method, with the corresponding intermediate of Structure 2 and the corresponding carboxylic acid as starting materials.

TABLE 66 t_(R) [min] MS-data Formula LC-MS m/z Intermediates of Structure 1 MW Method [M + H]⁺ {3-[6-Fluoro-2-((1R,2R)-2-phenyl- C30H30NO4F 1.01 488.3 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 487.22 LC-MS 3 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid ethyl ester {3-[7-Fluoro-2-((1R,2R)-2-phenyl- C30H30NO4F 1.00 488.3 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 487.22 LC-MS 3 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid ethyl ester (±)-(3-{5-Fluoro-2-[trans-2-(4-fluoro-phenyl)- C30H29NO4F2 1.02 506.2 cyclopropanecarbonyl]-1,2,3,4-tetrahydro- 505.21 LC-MS 3 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid ethyl ester (±)-(3-{2-[trans-2-(4-Chloro-phenyl)- C30H29NO4ClF 1.05 522.2 cyclopropanecarbonyl]-5-fluoro-1,2,3,4- 521.18 LC-MS 3 tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid ethyl ester (±)-(3-{2-[trans-2-(2-Chloro-phenyl)- C30H29NO4ClF 1.04 522.2 cyclopropanecarbonyl]-5-fluoro-1,2,3,4- 521.18 LC-MS 3 tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid ethyl ester (±)-(3-{2-[trans-2-(3-Chloro-phenyl)- C30H29NO4ClF 1.05 522.2 cyclopropanecarbonyl]-5-fluoro-1,2,3,4- 521.18 LC-MS 3 tetrahydro-isoquinolin-8-yl}-4-methoxy- phenyl)-acetic acid ethyl ester (±)-(3-{5-Fluoro-2-[trans-2-(2-fluoro-phenyl)- C30H29NO4F2 1.02 506.2 cyclopropanecarbonyl]-1,2,3,4-tetrahydro- 505.21 LC-MS 3 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid ethyl ester (±)-{3-[5-Fluoro-2-(trans-2-o-tolyl- C31H32NO4F 1.04 502.3 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 501.23 LC-MS 3 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid ethyl ester {3-[5,7-Difluoro-2-((1R,2R)-2-phenyl- C30H29NO4F2 1.01 506.2 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 505.21 LC-MS 3 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid ethyl ester (±)-{3-[7-Fluoro-2-(trans-2-phenyl- C29H28NO4F 0.99 474.4 cyclopropanecarbonyl)-2,3-dihydro-1H- 473.20 LC-MS 3 isoindol-4-yl]-4-methoxy-phenyl}-acetic acid ethyl ester (±)-{3-[9-Fluoro-3-(trans-2-phenyl- C31H32NO4F 1.01 502.4 cyclopropanecarbonyl)-2,3,4,5-tetrahydro- 501.23 LC-MS 3 1H-benzo[d]azepin-6-yl]-4-methoxy- phenyl}-acetic acid ethyl ester (±)-{4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro- C31H32NO5F 1.01 518.3 1,2,3,4-tetrahydro-isoquinolin-8-yl]-3- 517.23 LC-MS 3 methoxy-phenyl}-acetic acid ethyl ester

Method B: A solution of the amine[4-ethoxy-3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (185 mg, 0.51 mmol, 1.0 eq.) and (±)-isochroman-4-yl-acetic acid (103 mg, 0.51 mmol, 1.0 eq.) in DMF (6 mL) was treated with 4-(dimethylamino)pyridine (94 mg, 0.77 mmol, 1.5 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (147 mg, 0.77 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 2.5 hours. Formic acid was added (0.2 mL). The resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired intermediate of Structure 1 as a colorless oil.

Listed in Table 67 below are intermediates of Structure 1, prepared according to the above-mentioned method, with the corresponding intermediate of Structure 2 and the corresponding carboxylic acid as starting materials.

TABLE 67 t_(R) [min] Formula LC-MS MS-data m/z Intermediates of Structure 1 MW Method [M + H]⁺ (±)-{4-Ethoxy-3-[5-fluoro-2-(2-isochroman- C32H34NO5F 1.02 531.9 4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8- 531.24 LC-MS 3 yl]-phenyl}-acetic acid ethyl ester (±)-{3-[2-(2-2,3-Dihydro-benzofuran-3-yl- C31H32NO5F 1.03 518.2 acetyl)-5-fluoro-1,2,3,4-tetrahydro- 517.23 LC-MS 3 isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid ethyl ester (±)-{3-Ethoxy-4-[5-fluoro-2-(2-isochroman- C32H34NO5F 1.03 532.3 1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8- 531.24 LC-MS 3 yl]-phenyl}-acetic acid ethyl ester (±)-{4-Ethoxy-3-[5-fluoro-2-(2-methyl-3- C31H34NO4F 1.04 504.2 phenyl-propionyl)-1,2,3,4-tetrahydro- 503.25 LC-MS 3 isoquinolin-8-yl]-phenyl}-acetic acid ethyl ester (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro- C31H33NO4F2 1.04 522.2 phenyl)-butyryl]-1,2,3,4-tetrahydro- 521.24 LC-MS 3 isoquinolin-8-yl}-phenyl)-acetic acid ethyl ester

Chiral Separation

Listed in table 68 are mixtures of enantiomers which were separated by prep. HPLC over a chiral stationary phase. Conditions for the separation are:

Method CS1:

Column ChiralPak AD-H (20×250 mm, 5 μm), eluent A 80% Heptane and eluent B 20% EtOH, flow 16 mL/min. Detection at 210 nm.

Method CS2:

Column ChiralPak AY-H (20×250 mm, 5 μm), eluent A 80% Heptane and eluent B 20% EtOH, flow 20 mL/min. Detection at 210 nm.

Method CS3:

Column ChiralPak IA (20×250 mm, 5 μm), eluent A 90% Heptane and eluent B 10% EtOH/DCM (1:2), flow 16 mL/min. Detection at 218 nm.

Method CS4:

Column Regis (R,R) Whelk-01 (21.1×250 mm, 5 μm), eluent A 50% Heptane and eluent B 50% EtOH, flow 20 mL/min. Detection at 210 nm.

Method CS5:

Column Regis (R,R) Whelk-01 (21.1×250 mm, 5 μm), eluent A 25% Heptane and eluent B 75% EtOH, flow 20 mL/min. Detection at 210 nm.

Method CS6:

Column Regis (R,R) Whelk-01 (21.1×250 mm, 5 μm), eluent A 70% Heptane and eluent B 30% AcOEt+1% DEA, flow 16 mL/min. Detection at 273 nm.

Method CS7:

Column ChiralPak IA (20×250 mm, 5 μm), eluent A 50% DCM and eluent B 50% heptane, flow 20 mL/min. Detection at 281 nm.

TABLE 68 Formula t_(R) [min] MW LC-MS HPLC Method Optically pure Method MS-data Mixture intermediates t_(R) [min] m/z [M + H]⁺ (±)-5-Fluoro-8-[2-methoxy- 5-Fluoro-8-[2-methoxy-4-(1- C28H28NO6F 1.03 4-(1-methoxycarbonyl- methoxycarbonyl-ethoxy)- 493.19 LC-MS 3 ethoxy)-phenyl]-3,4-dihydro- phenyl]-3,4-dihydro-1H- CS1 494.3 1H-isoquinoline-2- isoquinoline-2-carboxylic acid 10.83 carboxylic acid benzyl ester benzyl ester (enantiomer 1) (±)-5-Fluoro-8-[2-methoxy- 5-Fluoro-8-[2-methoxy-4-(1- C28H28NO6F 1.03 4-(1-methoxycarbonyl- methoxycarbonyl-ethoxy)- 493.19 LC-MS 3 ethoxy)-phenyl]-3,4-dihydro- phenyl]-3,4-dihydro-1H- CS1 494.3 1H-isoquinoline-2- isoquinoline-2-carboxylic acid 13.59 carboxylic acid benzyl ester benzyl ester (enantiomer 2) (±)-{4-[2-(2-Chroman-4-yl- {4-[2-(2-Chroman-4-yl- C31H32NO5F 1.01 acetyl)-5-fluoro-1,2,3,4- acetyl)-5-fluoro-1,2,3,4- 517.23 LC-MS 3 tetrahydro-isoquinolin-8-yl]- tetrahydro-isoquinolin-8-yl]-3- CS1 518.3 3-methoxy-phenyl}-acetic methoxy-phenyl}-acetic acid 12.13 acid ethyl ester ethyl ester (enantiomer 1) (±)-{4-[2-(2-Chroman-4-yl- {4-[2-(2-Chroman-4-yl- C31H32NO5F 1.01 acetyl)-5-fluoro-1,2,3,4- acetyl)-5-fluoro-1,2,3,4- 517.23 LC-MS 3 tetrahydro-isoquinolin-8-yl]- tetrahydro-isoquinolin-8-yl]-3- CS1 518.3 3-methoxy-phenyl}-acetic methoxy-phenyl}-acetic acid 14.44 acid ethyl ester ethyl ester (enantiomer 2) (±)-{4-Ethoxy-3-[5-fluoro-2- {4-Ethoxy-3-[5-fluoro-2-(2- C32H34NO5F 1.01 (2-isochroman-4-yl-acetyl)- isochroman-4-yl-acetyl)- 531.24 LC-MS 3 1,2,3,4-tetrahydro- 1,2,3,4-tetrahydro- CS2 532.2 isoquinolin-8-yl]-phenyl}- isoquinolin-8-yl]-phenyl}- 10.61 acetic acid ethyl ester acetic acid ethyl ester (enantiomer 1) (±)-{4-Ethoxy-3-[5-fluoro-2- {4-Ethoxy-3-[5-fluoro-2-(2- C32H34NO5F 1.01 (2-isochroman-4-yl-acetyl)- isochroman-4-yl-acetyl)- 531.24 LC-MS 3 1,2,3,4-tetrahydro- 1,2,3,4-tetrahydro- CS2 532.2 isoquinolin-8-yl]-phenyl}- isoquinolin-8-yl]-phenyl}- 14.98 acetic acid ethyl ester acetic acid ethyl ester (enantiomer 2) (±)-{3-[2-(2-2,3-Dihydro- {3-[2-(2-2,3-Dihydro- C31H32NO5F 1.02 benzofuran-3-yl-acetyl)-5- benzofuran-3-yl-acetyl)-5- 517.23 LC-MS 3 fluoro-1,2,3,4-tetrahydro- fluoro-1,2,3,4-tetrahydro- CS3 518.2 isoquinolin-8-yl]-4-ethoxy- isoquinolin-8-yl]-4-ethoxy- 12.24 phenyl}-acetic acid ethyl phenyl}-acetic acid ethyl ester ester (enantiomer 1) (±)-{3-[2-(2-2,3-Dihydro- {3-[2-(2-2,3-Dihydro- C31H32NO5F 1.02 benzofuran-3-yl-acetyl)-5- benzofuran-3-yl-acetyl)-5- 517.23 LC-MS 3 fluoro-1,2,3,4-tetrahydro- fluoro-1,2,3,4-tetrahydro- CS3 518.2 isoquinolin-8-yl]-4-ethoxy- isoquinolin-8-yl]-4-ethoxy- 14.07 phenyl}-acetic acid ethyl phenyl}-acetic acid ethyl ester ester (enantiomer 2) (±)-{3-Ethoxy-4-[5-fluoro-2- {3-Ethoxy-4-[5-fluoro-2-(2- C32H34NO5F 1.02 (2-isochroman-1-yl-acetyl)- isochroman-1-yl-acetyl)- 531.24 LC-MS 3 1,2,3,4-tetrahydro- 1,2,3,4-tetrahydro- CS4 532.2 isoquinolin-8-yl]-phenyl}- isoquinolin-8-yl]-phenyl}- 15.72 acetic acid ethyl ester acetic acid ethyl ester (enantiomer 1) (±)-{3-Ethoxy-4-[5-fluoro-2- {3-Ethoxy-4-[5-fluoro-2-(2- C32H34NO5F 1.02 (2-isochroman-1-yl-acetyl)- isochroman-1-yl-acetyl)- 531.24 LC-MS 3 1,2,3,4-tetrahydro- 1,2,3,4-tetrahydro- CS4 532.2 isoquinolin-8-yl]-phenyl}- isoquinolin-8-yl]-phenyl}- 19.20 acetic acid ethyl ester acetic acid ethyl ester (enantiomer 2) (±)-{4-Ethoxy-3-[5-fluoro-2- {4-Ethoxy-3-[5-fluoro-2-(3- C30H33N2O4F 0.80 (3-pyridin-2-yl-butyryl)- pyridin-2-yl-butyryl)-1,2,3,4- 504.24 LC-MS 3 1,2,3,4-tetrahydro- tetrahydro-isoquinolin-8-yl]- CS5 505.3 isoquinolin-8-yl]-phenyl}- phenyl}-acetic acid ethyl 8.93 acetic acid ethyl ester ester (enantiomer 1) (±)-{4-Ethoxy-3-[5-fluoro-2- {4-Ethoxy-3-[5-fluoro-2-(3- C30H33N2O4F 0.80 (3-pyridin-2-yl-butyryl)- pyridin-2-yl-butyryl)-1,2,3,4- 504.24 LC-MS 3 1,2,3,4-tetrahydro- tetrahydro-isoquinolin-8-yl]- CS5 505.3 isoquinolin-8-yl]-phenyl}- phenyl}-acetic acid ethyl 11.66 acetic acid ethyl ester ester (enantiomer 2) (±)-(4-Ethoxy-3-{5-fluoro-2- (4-Ethoxy-3-{5-fluoro-2-[3-(4- C31H33NO4F2 1.04 [3-(4-fluoro-phenyl)-butyryl]- fluoro-phenyl)-butyryl]- 521.24 LC-MS 3 1,2,3,4-tetrahydro- 1,2,3,4-tetrahydro- CS6 522.2 isoquinolin-8-yl}-phenyl)- isoquinolin-8-yl}-phenyl)- 13.80 acetic acid ethyl ester acetic acid ethyl ester (enantiomer 1) (±)-(4-Ethoxy-3-{5-fluoro-2- (4-Ethoxy-3-{5-fluoro-2-[3-(4- C31H33NO4F2 1.04 [3-(4-fluoro-phenyl)-butyryl]- fluoro-phenyl)-butyryl]- 521.24 LC-MS 3 1,2,3,4-tetrahydro- 1,2,3,4-tetrahydro- CS6 522.2 isoquinolin-8-yl}-phenyl)- isoquinolin-8-yl}-phenyl)- 16.07 acetic acid ethyl ester acetic acid ethyl ester (enantiomer 2) (±)-{4-Ethoxy-3-[5-fluoro-2- {4-Ethoxy-3-[5-fluoro-2-(2- C31H34NO4F 1.04 (2-methyl-3-phenyl- methyl-3-phenyl-propionyl)- 503.25 LC-MS 3 propionyl)-1,2,3,4- 1,2,3,4-tetrahydro- CS7 504.2 tetrahydro-isoquinolin-8-yl]- isoquinolin-8-yl]-phenyl}- 4.55 phenyl}-acetic acid ethyl acetic acid ethyl ester ester (enantiomer 1) (±)-{4-Ethoxy-3-[5-fluoro-2- {4-Ethoxy-3-[5-fluoro-2-(2- C31H34NO4F 1.04 (2-methyl-3-phenyl- methyl-3-phenyl-propionyl)- 503.25 LC-MS 3 propionyl)-1,2,3,4- 1,2,3,4-tetrahydro- CS7 504.2 tetrahydro-isoquinolin-8-yl]- isoquinolin-8-yl]-phenyl}- 7.04 phenyl}-acetic acid ethyl acetic acid ethyl ester ester (enantiomer 2)

Biological Assays: Preparation of hCRTH2 Receptor Membranes and Radioligand Displacement Assay:

First, recombinant HEK293-hCRTH₂ cells were detached from culture plates into 5 ml buffer A/plate (Buffer A: 5 mM Tris, 1 mM MgCl₂-6H₂O pH=7.4) using a rubber policeman. Cells were then transferred into centrifugation tubes and centrifuged for 5 min at 400 g. The cell pellet was resuspended in the same buffer and tubes were frozen at −80° C. Cells were thawed and membrane fragments were generated by homogenization using a polytron homogenizer (30 seconds). The membrane fragments were then centrifuged at 3000 g for 20 minutes and resuspended in buffer C (Buffer C: 75 mM Tris, 25 mM MgCl₂, 250 mM Saccharose pH 7.4). Aliquots of membrane fragments were stored at −20° C.

Binding assay was performed in a final assay volume of 250 μl. First, 25 μl of test compound, previously diluted in Binding-Buffer (Binding-Buffer: 50 mM Tris-Base, 100 mM NaCl, 1 mM EDTA, 0.1% BSA (protease free), 0.01% NaN₃, 10 mM MnCl₂, pH 7.0) was placed into each well. After addition of 75 μl Binding-Buffer, 50 μl of the radioligand ³H-PGD₂ (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well. Binding assay was started by addition of 100 μl CRTH₂ membrane fragments, reaching a final concentration of 20 μg/well. For non-specific binding, PGD₂ was added to the reaction mixture to 10 mM final concentration. This assay mix was incubated for 90 minutes at room temperature and then filtered through a GF/C filter 96-well plate which was pre-soaked for 3 hours in 0.5% polyethyleneimine (PEI). The filter-wells were washed three times with ice cold Binding-Buffer. Then, 40 μl of Microscint-40 (Packard) was added to each well and the retained radioactivity quantified in a Topcount (Packard).

Antagonistic activities of exemplified compounds are displayed in the following Table:

IC₅₀ Example Name [nM] 1 (±)-(3-{5-Fluoro-2-[trans-2-(4-fluoro-phenyl)- 1.99 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 2 (±)-(3-{2-[trans-2-(4-Chloro-phenyl)-cyclopropanecarbonyl]-5- 1.93 fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 3 (±)-(3-{2-[trans-2-(2-Chloro-phenyl)-cyclopropanecarbonyl]-5- 2.11 fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 4 (±)-(3-{2-[trans-2-(3-Chloro-phenyl)-cyclopropanecarbonyl]-5- 5.39 fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 5 (±)-(3-{5-Fluoro-2-[trans-2-(2-fluoro-phenyl)- 3.64 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 6 (±)-{3-[5-Fluoro-2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4- 4.22 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 7 8-(5-Carboxymethyl-2-methyl-phenyl)-5-fluoro-3,4-dihydro-1H- 25.6 isoquinoline-2-carboxylic acid benzyl ester 8 8-(5-Carboxymethyl-2-trifluoromethyl-phenyl)-5-fluoro-3,4- 7.31 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 9 8-(5-Carboxymethyl-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 12.8 isoquinoline-2-carboxylic acid benzyl ester 10 8-(5-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H- 10.1 isoquinoline-2-carboxylic acid benzyl ester 11 8-(3-Carboxymethyl-4-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 69.1 isoquinoline-2-carboxylic acid benzyl ester 12 8-(3-Carboxymethyl-4-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H- 21.8 isoquinoline-2-carboxylic acid benzyl ester 13 8-(3-Carboxymethyl-4-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 72.3 isoquinoline-2-carboxylic acid benzyl ester 14 8-(3-Carboxymethyl-5-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H- 14.8 isoquinoline-2-carboxylic acid benzyl ester 15 8-(3-Carboxymethyl-5-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 18.5 isoquinoline-2-carboxylic acid benzyl ester 16 8-(3-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H- 25.2 isoquinoline-2-carboxylic acid benzyl ester 17 6-(5-Carboxymethyl-2-methoxy-phenyl)-9-fluoro-1,2,4,5- 141 tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester 18 4-(5-Carboxymethyl-2-methoxy-phenyl)-7-fluoro-1,3-dihydro- 165 isoindole-2-carboxylic acid benzyl ester 19 8-(3-Carboxymethyl-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 20.2 isoquinoline-2-carboxylic acid benzyl ester 20 8-(5-Carboxymethyl-2-methanesulfonyl-phenyl)-5-fluoro-3,4- 16.3 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 21 8-(5-Carboxymethyl-2-trifluoromethoxy-phenyl)-5-fluoro-3,4- 2.19 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 22 8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro- 4.72 1H-isoquinoline-2-carboxylic acid benzyl ester 23 8-(5-Carboxymethyl-2-fluoro-phenyl)-3,4-dihydro-1H- 192 isoquinoline-2-carboxylic acid benzyl ester 24 8-(3-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H- 69.5 isoquinoline-2-carboxylic acid benzyl ester 25 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methanesulfonyl-3,4- 149 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 26 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 3.07 tetrahydro-isoquinolin-8-yl]-4-trifluoromethoxy-phenyl}-acetic acid 27 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 12.9 tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 28 {4-Chloro-3-[5-fluoro-2-((1R,2R)-2-phenyl- 10.0 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 29 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 6.6 tetrahydro-isoquinolin-8-yl]-4-methanesulfonyl-phenyl}-acetic acid 30 8-(2-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H- 875 isoquinoline-2-carboxylic acid benzyl ester 31 8-(5-Carboxymethyl-2-methoxy-phenyl)-5,6-difluoro-3,4-dihydro- 12 1H-isoquinoline-2-carboxylic acid benzyl ester 32 8-(5-Carboxymethyl-2-methoxy-phenyl)-6-fluoro-3,4-dihydro-1H- 10.5 isoquinoline-2-carboxylic acid benzyl ester 33 8-(5-Carboxymethyl-2-methoxy-phenyl)-7-fluoro-3,4-dihydro-1H- 113 isoquinoline-2-carboxylic acid benzyl ester 34 {3-[6-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 2.7 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 35 {3-[7-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 3.19 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 36 (±)-{3-[9-Fluoro-3-(trans-2-phenyl-cyclopropanecarbonyl)-2,3,4,5- 19.9 tetrahydro-1H-benzo[d]azepin-6-yl]-4-methoxy-phenyl}-acetic acid 37 (±)-{3-[7-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-2,3- 7.54 dihydro-1H-isoindol-4-yl]-4-methoxy-phenyl}-acetic acid 38 {3-[5,7-Difluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)- 11.2 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 39 8-(5-Carboxymethyl-2-methoxy-phenyl)-5,7-difluoro-3,4-dihydro- 5.89 1H-isoquinoline-2-carboxylic acid benzyl ester 40 8-(4-Carboxymethyl-3-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 29.1 isoquinoline-2-carboxylic acid benzyl ester 41 8-(4-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H- 44.9 isoquinoline-2-carboxylic acid benzyl ester 42 (3-{5-Fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4- 8.76 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 43 {3-[5-Fluoro-2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin- 30.2 8-yl]-4-methoxy-phenyl}-acetic acid 44 (3-{5-Fluoro-2-[2-(4-fluoro-phenoxy)-acetyl]-1,2,3,4-tetrahydro- 59.1 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 45 (3-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 2.9 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 46 {3-[2-(2-Ethoxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8- 774 yl]-4-methoxy-phenyl}-acetic acid 47 {3-[2-(2-tert-Butoxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 551 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 48 (±)-(3-{5-Fluoro-2-[trans-2-(3-fluoro-phenyl)- 12 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 49 (3-{5-Fluoro-2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]- 54 1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 50 {3-[5-Fluoro-2-(2,2,3,3-tetramethyl-cyclopropanecarbonyl)- 267 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 51 {3-[5-Fluoro-2-(3-pyridin-3-yl-propionyl)-1,2,3,4-tetrahydro- 57.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 52 [3-(2-Cyclopropanecarbonyl-5-fluoro-1,2,3,4-tetrahydro- 68.9 isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid 53 {3-[2-(3-3,4-Dihydro-2H-quinolin-1-yl-propionyl)-5-fluoro-1,2,3,4- 4.49 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 54 {3-[5-Fluoro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro- 5.83 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 55 (±)-{3-[2-(2,2-Dimethyl-cyclopropanecarbonyl)-5-fluoro-1,2,3,4- 45.7 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 56 {3-[5-Fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin- 42.1 8-yl]-4-methoxy-phenyl}-acetic acid 57 (3-{5-Fluoro-2-[3-(3-methyl-indol-1-yl)-propionyl]-1,2,3,4- 16.2 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 58 (3-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro- 3.57 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 59 {3-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-5-fluoro-1,2,3,4- 7.4 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 60 (±)-{3-[5-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 2.64 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 61 (3-{5-Fluoro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 8.0 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 62 (3-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 4.74 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 63 (3-{5-Fluoro-2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-1,2,3,4- 29.5 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 64 (3-{2-[(1R,2R)-2-(4-Chloro-phenyl)-cyclopropanecarbonyl]-5- 1.12 fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 65 (3-{5-Fluoro-2-[(1R,2R)-2-(3-fluoro-phenyl)- 1.85 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 66 (3-{5-Fluoro-2-[(1R,2R)-2-(2-fluoro-phenyl)- 1.77 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 67 {3-[5-Fluoro-2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro- 21.6 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 68 (3-{5-Chloro-2-[(1R,2R)-2-(4-chloro-phenyl)- 3.75 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 69 (3-{5-Chloro-2-[(1R,2R)-2-(3-fluoro-phenyl)- 9.58 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 70 (3-{5-Chloro-2-[(1R,2R)-2-(2-fluoro-phenyl)- 1.16 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 71 {3-[5-Chloro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 1.68 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 72 {3-[5-Chloro-2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro- 37.8 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 73 (3-{5-Chloro-2-[2-(2-chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro- 30.2 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 74 (3-{5-Chloro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 10.5 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 75 (3-{5-Chloro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 38.4 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 76 {3-[5-Chloro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro- 43.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 77 {3-[5-Chloro-2-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-1,2,3,4- 24.0 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 78 {3-[5-Chloro-2-(3-2,3-dihydro-indol-1-yl-propionyl)-1,2,3,4- 61.5 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 79 (3-{5-Chloro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 37.8 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 80 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 1.89 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 81 {3-[5-Fluoro-2-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 33.1 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 82 [3-(2-Cyclopropanecarbonyl-5-trifluoromethyl-1,2,3,4-tetrahydro- 250 isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid 83 (±)-{4-Methoxy-3-[2-(trans-2-phenyl-cyclopropanecarbonyl)-5- 26.1 trifluoromethyl-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 84 {3-[5,6-Difluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)- 4.82 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 85 (3-{5-Fluoro-2-[(E)-(3-phenyl-acryloyl)]-1,2,3,4-tetrahydro- 35.8 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 86 (3-{5-Fluoro-2-[(E)-3-(6-methoxy-pyridin-3-yl)-acryloyl]-1,2,3,4- 70.5 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 87 (3-{2-[(E)-3-(2,4-Dimethyl-thiazol-5-yl)-acryloyl]-5-fluoro-1,2,3,4- 93.8 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 88 {3-[2-((E)-3-Benzothiazol-2-yl-acryloyl)-5-fluoro-1,2,3,4- 9.14 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 89 {3-[5-Fluoro-2-((E)-3-pyridin-3-yl-acryloyl)-1,2,3,4-tetrahydro- 57.2 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 90 (3-{2-[(E)-3-(2,5-Dimethyl-2H-pyrazol-3-yl)-acryloyl]-5-fluoro- 49.1 1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 91 {3-[5-Fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro- 32.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 92 (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4- 15.7 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 93 {3-[5-Fluoro-2-(3-pyrimidin-2-yl-propionyl)-1,2,3,4-tetrahydro- 690 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 94 (3-{5-Fluoro-2-[2-(pyridin-3-yloxy)-acetyl]-1,2,3,4-tetrahydro- 418 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 95 (±)-(3-{5-Fluoro-2-[trans-2-(2-trifluoromethyl-phenyl)- 0.22 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 96 (±)-(3-{5-Fluoro-2-[trans-2-(4-methoxy-phenyl)- 21.2 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 97 (±)-(3-{2-[3-(4-Chloro-phenyl)-3-phenyl-propionyl]-5-fluoro- 48.1 1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 98 (±)-(3-{2-[trans-2-(2,4-Dichloro-phenyl)-cyclopropanecarbonyl]-5- 10.1 fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 99 {3-[8-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 414 tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid 100 {3-[8-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-5- 105 yl]-4-methoxy-phenyl}-acetic acid 101 {3-[8-Fluoro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro- 64.7 isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid 102 {3-[8-Fluoro-2-(3-phenoxy-propionyl)-1,2,3,4-tetrahydro- 43 isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid 103 (3-{2-[2-(2-Chloro-benzyloxy)-acetyl]-8-fluoro-1,2,3,4-tetrahydro- 69.2 isoquinolin-5-yl}-4-methoxy-phenyl)-acetic acid 104 {3-[2-(3-3,4-Dihydro-2H-quinolin-1-yl-propionyl)-8-fluoro-1,2,3,4- 21.3 tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid 105 (3-{8-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 17.7 tetrahydro-isoquinolin-5-yl}-4-methoxy-phenyl)-acetic acid 106 {3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 10.4 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 107 {3-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 18.3 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 108 {3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 10.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 109 (±)-{3-[5-Fluoro-2-(2-methyl-3-phenyl-propionyl)-1,2,3,4- 28.9 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 110 {3-[5-Fluoro-2-(indane-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin- 172 8-yl]-4-methoxy-phenyl}-acetic acid 111 {3-[5-Fluoro-2-(2-indan-2-yl-acetyl)-1,2,3,4-tetrahydro- 8.11 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 112 (±)-{3-[5-Fluoro-2-(indane-1-carbonyl)-1,2,3,4-tetrahydro- 202 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 113 (±)-{3-[2-(Chroman-3-carbonyl)-5-fluoro-1,2,3,4-tetrahydro- 18.6 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 114 (±)-{3-[5-Fluoro-2-(4-oxo-1,2,3,4-tetrahydro-naphthalene-2- 21.2 carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 115 (±)-{3-[2-(Chroman-2-carbonyl)-5-fluoro-1,2,3,4-tetrahydro- 173 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 116 (±)-{3-[2-(Bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-5-fluoro- 211 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 117 {3-[5-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8- 5.41 yl]-4-methoxy-phenyl}-acetic acid 118 {3-[5-Fluoro-2-(4-oxo-4-phenyl-butyryl)-1,2,3,4-tetrahydro- 38.6 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 119 (3-{5-Fluoro-2-[2-(1-methyl-1H-indol-3-yl)-acetyl]-1,2,3,4- 69.5 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 120 (±)-2-{3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)- 8.56 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-propionic acid 121 {3-[2-(2-Benzo[d]isoxazol-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 47.2 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 122 (±)-{3-[5-Fluoro-2-(3-oxo-indane-1-carbonyl)-1,2,3,4-tetrahydro- 862 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 123 (±)-{3-[5-Fluoro-2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)- 37.7 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 124 {3-[5-Fluoro-2-(2-1H-indazol-3-yl-acetyl)-1,2,3,4-tetrahydro- 10.5 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 125 (3-{5-Fluoro-2-[3-(3-methyl-indazol-1-yl)-propionyl]-1,2,3,4- 16.3 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 126 (3-{5-Fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4- 9.54 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 127 {3-[2-(2-Cyclohexyl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 176 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 128 (3-{5-Fluoro-2-[2-(1-hydroxy-cyclohexyl)-acetyl]-1,2,3,4- 538 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 129 {3-[2-(3,3-Dimethyl-butyryl)-5-fluoro-1,2,3,4-tetrahydro- 913 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 130 {3-[5-Fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 17.7 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 131 {3-[5-Fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 60.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 132 {3-[5-Fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 15.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 133 [3-(5-Fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro- 13 isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid 134 {3-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro- 21.5 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 135 {3-[5-Fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro- 19.6 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 136 [3-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8- 30.6 yl)-4-methoxy-phenyl]-acetic acid 137 [3-(5-Fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8- 764 yl)-4-methoxy-phenyl]-acetic acid 138 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 5.42 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 139 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.53 isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester 140 (±)-8-[5-(1-Carboxy-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4- 62.6 dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 141 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 187 isoquinoline-2-carboxylic acid ethyl ester 142 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 148 isoquinoline-2-carboxylic acid isobutyl ester 143 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 348 isoquinoline-2-carboxylic acid isopropyl ester 144 8-(3-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 86.2 isoquinoline-2-carboxylic acid benzyl ester 145 8-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 430 isoquinoline-2-carboxylic acid benzyl ester 146 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.06 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 147 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.51 isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester 148 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 51.6 isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester 149 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 6.87 isoquinoline-2-carboxylic acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester 150 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 7.12 isoquinoline-2-carboxylic acid 2-methyl-thiazol-4-ylmethyl ester 151 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 5.73 isoquinoline-2-carboxylic acid 2-methyl-thiazol-5-ylmethyl ester 152 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 34.1 isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester 153 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 40.7 isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5-yl)-ethyl ester 154 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-chloro-3,4-dihydro-1H- 5.9 isoquinoline-2-carboxylic acid benzyl ester 155 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methyl-3,4-dihydro-1H- 46.8 isoquinoline-2-carboxylic acid benzyl ester 156 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methoxy-3,4-dihydro- 251 1H-isoquinoline-2-carboxylic acid benzyl ester 157 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 11.7 isoquinoline-2-carboxylic acid benzyl ester 158 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-trifluoromethyl-3,4- 67.8 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 159 5-(5-Carboxymethyl-2-methoxy-phenyl)-8-fluoro-3,4-dihydro-1H- 594 isoquinoline-2-carboxylic acid benzyl ester 160 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 0.67 tetrahydro-isoquinolin-8-yl]-4-trifluoromethoxy-phenoxy}-acetic acid 161 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 1.38 tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenoxy}-acetic acid 162 8-(5-Carboxymethoxy-2-trifluoromethoxy-phenyl)-5-fluoro-3,4- 2.47 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 163 8-(5-Carboxymethoxy-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro- 7.94 1H-isoquinoline-2-carboxylic acid benzyl ester 164 8-(4-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H- 47.3 isoquinoline-2-carboxylic acid benzyl ester 165 8-(4-Carboxymethyl-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 26.3 isoquinoline-2-carboxylic acid benzyl ester 166 8-(4-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 4.5 isoquinoline-2-carboxylic acid benzyl ester 167 8-(6-Carboxymethyl-benzo[1,3]dioxol-4-yl)-5-fluoro-3,4-dihydro- 15.4 1H-isoquinoline-2-carboxylic acid benzyl ester 168 8-(7-Carboxymethyl-2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-fluoro- 17.9 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 169 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-cyano-3,4-dihydro-1H- 9.17 isoquinoline-2-carboxylic acid benzyl ester 170 8-(5-Carboxymethyl-2-methoxy-phenyl)-3,4-dihydro-1H- 110 isoquinoline-2-carboxylic acid benzyl ester 171 (±)-8-[5-(1-Carboxy-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4- 21.2 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 172 8-(4-Carboxymethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 209 isoquinoline-2-carboxylic acid benzyl ester 173 8-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 91.4 isoquinoline-2-carboxylic acid benzyl ester 174 8-[2-(3-Carboxy-propoxy)-5-fluoro-phenyl]-3,4-dihydro-1H- 289 isoquinoline-2-carboxylic acid benzyl ester 175 8-(3-Carboxymethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 117 isoquinoline-2-carboxylic acid benzyl ester 176 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 13.6 isoquinoline-2-carboxylic acid benzyl ester 177 8-(5-Carboxymethoxy-2-methoxy-phenyl)-5-fluoro-3,4-dihydro- 21.3 1H-isoquinoline-2-carboxylic acid benzyl ester 178 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-chloro-3,4-dihydro-1H- 17.5 isoquinoline-2-carboxylic acid benzyl ester 179 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-methyl-3,4-dihydro-1H- 250 isoquinoline-2-carboxylic acid benzyl ester 180 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-trifluoromethyl-3,4- 208 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 181 8-(5-Carboxymethoxy-2-chloro-phenyl)-3,4-dihydro-1H- 123 isoquinoline-2-carboxylic acid benzyl ester 182 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 4.36 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenoxy}-acetic acid 183 (4-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 0.46 tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 184 {4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 0.90 tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 185 (4-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 1.28 isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 186 (4-{5-Fluoro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 2.66 tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 187 {4-[5-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8- 0.89 yl]-3-methoxy-phenyl}-acetic acid 188 {4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 0.53 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 189 {4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 1.04 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 190 (4-{5-Fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4- 7.25 tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 191 {4-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-5-fluoro-1,2,3,4- 2.42 tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 192 (4-{5-Fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4- 0.69 tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 193 (4-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro- 1.38 isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 194 {4-[5-Fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin- 0.75 8-yl]-3-methoxy-phenyl}-acetic acid 195 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 1.06 isoquinoline-2-carboxylic acid benzyl ester 196 8-(5-Carboxymethyl-2-cyclopropylmethoxy-phenyl)-5-fluoro-3,4- 0.28 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 197 8-(5-Carboxymethyl-2-propoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 0.28 isoquinoline-2-carboxylic acid benzyl ester 198 8-(5-Carboxymethyl-2-isobutoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 1.28 isoquinoline-2-carboxylic acid benzyl ester 199 8-[5-Carboxymethyl-2-(2-methoxy-ethoxy)-phenyl]-5-fluoro-3,4- 0.49 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 200 {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 8.0 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid (enantiomer 1) 201 {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 9.5 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid (enantiomer 2) 202 8-[4-(1-Carboxy-ethoxy)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro- 179 1H-isoquinoline-2-carboxylic acid benzyl ester (enantiomer 2) 203 {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 2.9 isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 1) 204 {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 2.9 isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 205 {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 1.0 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 1) 206 {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 2.4 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 207 {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 1.4 tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid (enantiomer 1) 208 {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 1.6 tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid (enantiomer 2) 209 {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4- 3.4 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 1) 210 {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4- 5.5 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 211 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-butyryl]-1,2,3,4- 2.6 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid (enantiomer 1) 212 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-butyryl]-1,2,3,4- 11.4 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid (enantiomer 2) 213 {4-Ethoxy-3-[5-fluoro-2-(2-methyl-3-phenyl-propionyl)-1,2,3,4- 111 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 1) 214 {4-Ethoxy-3-[5-fluoro-2-(2-methyl-3-phenyl-propionyl)-1,2,3,4- 3.1 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 215 8-(5-Carboxymethyl-2-propyl-phenyl)-5-fluoro-3,4-dihydro-1H- 3.6 isoquinoline-2-carboxylic acid benzyl ester 216 8-(4-Carboxymethyl-2-isopropyl-phenyl)-5-fluoro-3,4-dihydro-1H- 19.4 isoquinoline-2-carboxylic acid benzyl ester 217 8-(4-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro- 2.3 1H-isoquinoline-2-carboxylic acid benzyl ester 218 8-(4-Carboxymethyl-2,6-dimethoxy-phenyl)-5-fluoro-3,4-dihydro- 1.7 1H-isoquinoline-2-carboxylic acid benzyl ester 219 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4- 9.1 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 220 {4-Ethoxy-3-[5-fluoro-2-((1R,2R)-2-phenyl- 13.5 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 221 {4-Ethoxy-3-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 1.2 isoquinolin-8-yl]-phenyl}-acetic acid 222 (4-Ethoxy-3-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4- 26.4 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 223 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]- 15 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 224 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 8.2 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 225 {4-Ethoxy-3-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4- 11.7 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 226 (±)-{3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 12.9 isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 227 (±)-{3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 0.9 tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 228 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4- 6.8 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 229 (±)-{3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 0.7 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 230 (3-Ethoxy-4-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4- 1.0 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 231 {3-Ethoxy-4-[5-fluoro-2-((1R,2R)-2-phenyl- 10.5 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 232 (±)-{3-Ethoxy-4-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4- 0.6 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 233 (±)-{3-Ethoxy-4-[5-fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4- 1.1 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 234 {3-Ethoxy-4-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 0.9 isoquinolin-8-yl]-phenyl}-acetic acid 235 (±)-{4-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 0.3 tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid 236 (±)-{4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 0.8 isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid 237 (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]- 0.3 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 238 {3-Ethoxy-4-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4- 0.6 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 239 (±)-(3-{5-Fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1- 28.4 yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 240 (±)-(3-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4- 3.6 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 241 (±)-{3-[5-Fluoro-2-(8-methoxy-1,2,3,4-tetrahydro-naphthalene-2- 8.3 carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}- acetic acid 242 (±)-{3-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 2.7 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 243 (±)-(3-{5-Fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4- 20.6 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 244 (±)-(3-{5-Fluoro-2-[2-(6-fluoro-chroman-4-yl)-acetyl]-1,2,3,4- 158 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 245 (±)-{3-[2-(3-Cyclopropyl-butyryl)-5-fluoro-1,2,3,4-tetrahydro- 399 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 246 (±)-(3-{5-Fluoro-2-[2-(8-fluoro-chroman-4-yl)-acetyl]-1,2,3,4- 22.3 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 247 (±)-{3-[5-Fluoro-2-(2-5,6,7,8-tetrahydro-isoquinolin-8-yl-acetyl)- 484 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid hydrochloride 248 (±)-(3-{5-Fluoro-2-[3-(6-methoxy-pyridin-2-yl)-butyryl]-1,2,3,4- 77.9 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid hydrochloride 249 (±)-(3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4- 40.4 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid hydrochloride 250 (3-{5-Fluoro-2-[2-(1-phenyl-cyclobutyl)-acetyl]-1,2,3,4-tetrahydro- 146 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 251 [3-(5-Fluoro-2-{2-[1-(4-fluoro-phenyl)-cyclobutyl]-acetyl}-1,2,3,4- 414 tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid 252 (3-{5-Fluoro-2-[3-(3-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4- 13.2 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 253 (±)-{3-[2-(2-{[(4-Chloro-phenyl)-phenyl-methyl]-methyl-amino}- 10.6 acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 254 {3-[2-(2-Cyclopropyl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 614 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 255 {3-[5-Fluoro-2-((R)-2-phenyl-propionyl)-1,2,3,4-tetrahydro- 981 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 256 (±)-{3-[5-Fluoro-2-(3-hydroxy-3-phenyl-butyryl)-1,2,3,4- 49.8 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 257 (±)-{3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro- 2.2 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 258 (3-{5-Fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4- 2.8 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 259 (±)-(3-{5-Fluoro-2-[2-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-1- 587 yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)- acetic acid 260 (±)-{3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-2-yl-acetyl)- 1.4 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 261 (±)-{3-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro- 3.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 262 (±)-{3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 8.4 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 263 (±)-{3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-1-yl-acetyl)- 4.9 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 264 (±)-{3-[5-Fluoro-2-(4-methyl-3-phenyl-pentanoyl)-1,2,3,4- 253 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 265 (±)-{3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 7.8 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 266 (±)-{3-[5-Fluoro-2-(3-pyridin-3-yl-butyryl)-1,2,3,4-tetrahydro- 32.7 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid formiate 267 (±)-{3-[5-Fluoro-2-(3-pyridin-4-yl-butyryl)-1,2,3,4-tetrahydro- 86.1 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid formiate 268 (±)-{3-[5-Fluoro-2-(3-phenyl-pentanoyl)-1,2,3,4-tetrahydro- 63.6 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 269 {3-[5-Fluoro-2-((R)-1,2,3,4-tetrahydro-naphthalene-1-carbonyl)- 95.7 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 270 (±)-{3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 25.3 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 271 (±)-{3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro- 22.3 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 272 (±)-{3-[2-(Chroman-4-carbonyl)-5-fluoro-1,2,3,4-tetrahydro- 262 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 273 (±)-{3-[5-Fluoro-2-(isochroman-1-carbonyl)-1,2,3,4-tetrahydro- 683 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 274 (±)-{3-[5-Fluoro-2-(isochroman-3-carbonyl)-1,2,3,4-tetrahydro- 58.2 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 275 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(3-fluoro-phenyl)-cyclopropyl]- 6.8 acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid 276 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(2-fluoro-phenyl)-cyclopropyl]- 35.9 acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid 277 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(4-fluoro-phenyl)-cyclopropyl]- 1.9 acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid 278 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-butyryl]-1,2,3,4- 3.9 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 279 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro-phenyl)-butyryl]-1,2,3,4- 6.9 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 280 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(2-fluoro-phenyl)-butyryl]-1,2,3,4- 3.4 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 281 (±)-{4-Ethoxy-3-[5-fluoro-2-(3-pyrazin-2-yl-butyryl)-1,2,3,4- 27.5 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 282 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(2-methoxy-phenyl)-butyryl]- 2.2 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 283 (±)-{4-Ethoxy-3-[5-fluoro-2-(3-thiazol-2-yl-butyryl)-1,2,3,4- 7.2 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 284 (±)-(3-{2-[2-(2,2-Dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4- 2.4 yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-ethoxy- phenyl)-acetic acid 285 (±)-[4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 3.5 isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 286 [4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 8.9 isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 287 [4-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 8.1 isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 288 (±)-[4-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 10.0 isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 289 [4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 1.4 tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]- acetic acid 290 (±)-{3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 5.0 isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 291 {3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 5.9 isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 292 {3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 2.5 isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 293 (±)-{3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 1.6 isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 294 (±)-(3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4- 3.2 tetrahydro-isoquinolin-8-yl}-4-isopropoxy-phenyl)-acetic acid 295 (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4- 1.7 tetrahydro-isoquinolin-8-yl}-4-isopropoxy-phenyl)-acetic acid 296 (±)-{3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro- 0.8 isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 297 (±)-{3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro- 1.9 isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 298 (±)-{3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 1.2 tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid 299 (±)-[3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 14.8 isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 300 [3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 14.8 isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 301 [3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 3.6 isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 302 (±)-[3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 8.1 isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 303 (±)-[3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4- 6.6 tetrahydro-isoquinolin-8-yl}-4-(2,2,2-trifluoro-ethoxy)-phenyl]- acetic acid 304 [3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4- 12.6 tetrahydro-isoquinolin-8-yl}-4-(2,2,2-trifluoro-ethoxy)-phenyl]- acetic acid 305 (±)-[3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro- 3.4 isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 306 (±)-[3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro- 7.4 isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 307 (±)-[3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 3.4 tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]- acetic acid 308 (±)-{4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-pentanoyl)-1,2,3,4- 13.1 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 309 (4-Ethoxy-3-{5-fluoro-2-[3-(3-methoxy-pyridin-2-yl)-propionyl]- 32.3 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 310 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-propionyl]-1,2,3,4- 1.7 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 311 (4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro-phenyl)-propionyl]-1,2,3,4- 3.9 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 312 (4-Ethoxy-3-{5-fluoro-2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4- 4.8 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 313 (±)-{3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-pentanoyl)-1,2,3,4- 7.8 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 314 (3-Ethoxy-4-{5-fluoro-2-[3-(3-methoxy-pyridin-2-yl)-propionyl]- 46.1 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 315 (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro-phenyl)-propionyl]-1,2,3,4- 5.1 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 316 (3-Ethoxy-4-{5-fluoro-2-[3-(3-fluoro-phenyl)-propionyl]-1,2,3,4- 2.1 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 317 (3-Ethoxy-4-{5-fluoro-2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4- 1.7 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 318 (±)-{3-[2-(3-Cyclopropyl-3-pyridin-2-yl-propionyl)-5-fluoro-1,2,3,4- 114 tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 319 (±)-{4-[2-(3-Cyclopropyl-3-pyridin-2-yl-propionyl)-5-fluoro-1,2,3,4- 36.3 tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid 320 (±)-(3-Ethoxy-4-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]- 11.7 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 321 (3-Ethoxy-4-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]- 7.3 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 322 (±)-{3-Ethoxy-4-[5-fluoro-2-(trans-2-pyridin-2-yl- 1.3 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 323 (±)-(4-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4- 1.8 tetrahydro-isoquinolin-8-yl}-3-ethoxy-phenyl)-acetic acid 324 (±)-{4-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 0.9 isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid 325 (±)-{3-Ethoxy-4-[5-fluoro-2-(8-methoxy-1,2,3,4-tetrahydro- 1.8 naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 326 (±)-(3-Ethoxy-4-{5-fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro- 2.0 naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 327 (±)-(3-Ethoxy-4-{5-fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]- 0.2 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 328 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]- 1.8 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 329 (4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]- 4.2 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 330 (±)-{4-Ethoxy-3-[5-fluoro-2-(trans-2-pyridin-2-yl- 0.6 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 331 (±)-(3-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4- 9.6 tetrahydro-isoquinolin-8-yl}-4-ethoxy-phenyl)-acetic acid 332 (±)-{3-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 11.8 isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 333 (±)-{4-Ethoxy-3-[5-fluoro-2-(8-methoxy-1,2,3,4-tetrahydro- 22.7 naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 334 (±)-(4-Ethoxy-3-{5-fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro- 10.2 naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}- phenyl)-acetic acid 335 (±)-(4-Ethoxy-3-{5-fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]- 0.9 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 336 {4-Ethoxy-3-[5-fluoro-2-((E)-3-pyridin-2-yl-acryloyl)-1,2,3,4- 3.8 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 337 (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-3-yl)- 30.4 acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 338 {3-Ethoxy-4-[5-fluoro-2-((E)-3-pyridin-2-yl-acryloyl)-1,2,3,4- 2.3 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 339 (3-Ethoxy-4-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-4-yl)- 12.7 acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 340 {4-Ethoxy-3-[5-fluoro-2-(2-pyridin-2-yl-acetyl)-1,2,3,4-tetrahydro- 897 isoquinolin-8-yl]-phenyl}-acetic acid 341 (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-4-yl)- 5.8 acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 342 {3-Ethoxy-4-[5-fluoro-2-(2-pyridin-2-yl-acetyl)-1,2,3,4-tetrahydro- 150 isoquinolin-8-yl]-phenyl}-acetic acid 343 (±)-{3-[5-Fluoro-2-(2-methyl-3-pyridin-3-yl-propionyl)-1,2,3,4- 291 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 344 (±)-{3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4- 0.9 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 345 (±)-{4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4- 4.8 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 346 (±)-{4-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 3.7 isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid 347 [4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 1.5 isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid 348 {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4- 2.7 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 349 {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4- 0.5 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 350 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-5,6,7,8-tetrahydro-quinolin-8-yl- 8.2 acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 351 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)- 3.1 1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 352 (±)-{3-Ethoxy-4-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)- 8.1 1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 353 (±)-{4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 1.2 isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid 354 {4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 4.2 isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid 355 {4-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 10.3 isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid 356 {4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 2.1 isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid 357 {4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 1.6 tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid 358 (4-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4- 1.1 tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 359 (±)-{4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 0.6 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 360 (±)-{4-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro- 6.1 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 361 (±)-{3-[5-Fluoro-2-(trans-2-pyridin-2-yl-cyclopropanecarbonyl)- 2.2 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 362 (±)-{3-[2-(2-1,3-Dihydro-isobenzofuran-1-yl-acetyl)-5-fluoro- 22.9 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 363 (3-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4- 2.4 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 364 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 6.0 isoquinoline-2-carboxylic acid (R)-1-phenyl-ethyl ester 365 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.9 isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 366 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 4.2 isoquinoline-2-carboxylic acid 3-fluoro-5-methyl-pyridin-2- ylmethyl ester 367 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 8.8 isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester 368 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 5.5 isoquinoline-2-carboxylic acid (S)-1-phenyl-ethyl ester 369 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 8.7 isoquinoline-2-carboxylic acid cyclopentylmethyl ester 370 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 7.0 isoquinoline-2-carboxylic acid 3-methyl-butyl ester 371 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 0.6 isoquinoline-2-carboxylic acid 6-methyl-pyridin-2-ylmethyl ester 372 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 5.5 isoquinoline-2-carboxylic acid cyclopropylmethyl ester 373 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 1.7 isoquinoline-2-carboxylic acid phenethyl ester 374 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 4.2 isoquinoline-2-carboxylic acid (R)-2-phenyl-propyl ester 375 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 8.7 isoquinoline-2-carboxylic acid 3-methyl-but-2-enyl ester 376 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 6.3 isoquinoline-2-carboxylic acid butyl ester 377 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.4 isoquinoline-2-carboxylic acid isobutyl ester 378 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 5.9 isoquinoline-2-carboxylic acid 2-methoxy-ethyl ester 379 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.5 isoquinoline-2-carboxylic acid 3-methyl-but-3-enyl ester 380 (±)-8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro- 4.2 1H-isoquinoline-2-carboxylic acid 2-methyl-butyl ester 381 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 28.8 isoquinoline-2-carboxylic acid but-3-ynyl ester 382 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 14 isoquinoline-2-carboxylic acid 3-hydroxy-3-methyl-butyl ester 383 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 19 isoquinoline-2-carboxylic acid 3-methoxy-3-methyl-butyl ester 384 (±)-8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro- 14.8 1H-isoquinoline-2-carboxylic acid tetrahydro-furan-2-ylmethyl ester 385 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 35.8 isoquinoline-2-carboxylic acid (R)-1-phenyl-ethyl ester 386 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.4 isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 387 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 8.0 isoquinoline-2-carboxylic acid 3-fluoro-5-methyl-pyridin-2- ylmethyl ester 388 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.8 isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester 389 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 16.7 isoquinoline-2-carboxylic acid (S)-1-phenyl-ethyl ester 390 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 0.8 isoquinoline-2-carboxylic acid 6-methyl-pyridin-2-ylmethyl ester 391 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 1.6 isoquinoline-2-carboxylic acid cyclopropylmethyl ester 392 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 5.9 isoquinoline-2-carboxylic acid cyclopentylmethyl ester 393 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 49.4 isoquinoline-2-carboxylic acid 3-methyl-butyl ester 394 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 1.2 isoquinoline-2-carboxylic acid pyridin-2-ylmethyl ester 395 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.7 isoquinoline-2-carboxylic acid pyridin-2-ylmethyl ester 396 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.6 isoquinoline-2-carboxylic acid cyclohexylmethyl ester 397 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 6.8 isoquinoline-2-carboxylic acid cyclohexylmethyl ester 398 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.4 isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester 399 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 4.7 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 400 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 12.8 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 401 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 4.5 isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester 402 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 4.3 isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester 403 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 1.7 isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester 404 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.3 isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester 405 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.7 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 406 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 7.7 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 407 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.1 isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester 408 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 2.0 isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester 409 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 3.9 isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester 410 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 26.0 isoquinoline-2-carboxylic acid benzyl ester 411 8-[4-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro- 1.0 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 412 8-(5-Carboxymethyl-2-difluoromethoxy-phenyl)-5-fluoro-3,4- 1.8 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 413 8-[5-Carboxymethyl-2-(2,2-difluoro-ethoxy)-phenyl]-5-fluoro-3,4- 0.8 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 414 (±)-8-[5-(1-Carboxy-ethoxy)-2-methoxy-phenyl]-5-fluoro-3,4- 430 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 415 (±)-8-[5-(1-Carboxy-propoxy)-2-methoxy-phenyl]-5-fluoro-3,4- 337 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 416 8-(2-Carboxymethyl-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H- 575 isoquinoline-2-carboxylic acid benzyl ester 417 8-(2-Carboxymethoxy-6-methoxy-phenyl)-5-fluoro-3,4-dihydro- 23.5 1H-isoquinoline-2-carboxylic acid benzyl ester 418 8-(2-Carboxymethyl-6-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 352 isoquinoline-2-carboxylic acid benzyl ester 419 8-(2-tert-Butoxy-5-carboxymethyl-phenyl)-5-fluoro-3,4-dihydro- 2.8 1H-isoquinoline-2-carboxylic acid benzyl ester 420 8-(5-Carboxymethyl-2-dimethylamino-phenyl)-5-fluoro-3,4- 2.4 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 421 8-[5-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro- 3.8 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 422 8-[5-Carboxymethyl-2-(2-fluoro-ethoxy)-phenyl]-5-fluoro-3,4- 8.5 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 423 8-(3-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 180 isoquinoline-2-carboxylic acid benzyl ester 424 8-(4-Carboxymethoxy-2-methoxy-phenyl)-5-fluoro-3,4-dihydro- 444 1H-isoquinoline-2-carboxylic acid benzyl ester 425 (±)-8-[4-(1-Carboxy-ethyl)-2-ethoxy-phenyl]-5-fluoro-3,4-dihydro- 11.3 1H-isoquinoline-2-carboxylic acid benzyl ester 426 [3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 1.9 tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]- acetic acid 427 {4-(2-Fluoro-ethoxy)-3-[5-fluoro-2-((1R,2R)-2-phenyl- 3.1 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 428 {4-tert-Butoxy-3-[5-fluoro-2-((1R,2R)-2-phenyl- 3.7 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 429 1-{3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)- 50.7 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}- cyclopropanecarboxylic acid 430 8-(5-Carboxymethyl-2-cyclopropoxy-phenyl)-5-fluoro-3,4-dihydro- 14.9 1H-isoquinoline-2-carboxylic acid benzyl ester 431 8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-cyano-3,4-dihydro- 1.4 1H-isoquinoline-2-carboxylic acid benzyl ester 432 {4-Ethoxy-3-[5-fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4- 5.3 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 433 {4-Ethoxy-3-[5-fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4- 59.3 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 434 {4-Ethoxy-3-[5-fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4- 0.7 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 435 [4-Ethoxy-3-(5-fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro- 2.6 isoquinolin-8-yl)-phenyl]-acetic acid 436 {3-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro- 5.4 isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 437 {4-Ethoxy-3-[5-fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4- 10.9 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 438 [3-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8- 3.7 yl)-4-ethoxy-phenyl]-acetic acid 439 [4-Ethoxy-3-(5-fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro- 126 isoquinolin-8-yl)-phenyl]-acetic acid 440 {3-Ethoxy-4-[5-fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4- 3.8 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 441 {3-Ethoxy-4-[5-fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4- 17.5 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 442 {3-Ethoxy-4-[5-fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4- 5.3 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 443 [3-Ethoxy-4-(5-fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro- 18.1 isoquinolin-8-yl)-phenyl]-acetic acid 444 {4-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro- 2.0 isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid 445 {3-Ethoxy-4-[5-fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4- 2.5 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 446 [4-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8- 4.7 yl)-3-ethoxy-phenyl]-acetic acid 447 [3-Ethoxy-4-(5-fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro- 78.2 isoquinolin-8-yl)-phenyl]-acetic acid 448 (3-Ethoxy-4-{5-fluoro-2-[(pyridin-2-ylmethyl)-carbamoyl]-1,2,3,4- 9.2 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 449 (4-Ethoxy-3-{5-fluoro-2-[(pyridin-2-ylmethyl)-carbamoyl]-1,2,3,4- 14.2 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid

Eosinophil Shape Change Assay with Human Plasma

After obtaining informed consent, blood samples were drawn by venipuncture according to the protocol approved by the ethics committee of Basel, Switzerland. Polymorphonuclear leukocytes (containing eosinophils, basophils and neutrophils) were isolated using the Polymorphprep™ method (Axis-Shield). In brief, anticoagulated whole blood was layered onto a Polymorphprep gradient (density 1.113 g/ml) and centrifuged at 500 g for 30 min. The polymorphonuclear cell fraction was harvested and depleted for erythrocytes by hypotonic saline lysis.

The polymorphonuclear cells were resuspended in assay buffer (1×PBS with Ca²⁺/Mg²⁺ supplemented with 0.1% BSA, 10 mM HEPES, and 10 mM Glucose, pH 7.4) at 5×10⁶ cells/ml and stained with anti-CD49d-APC ((APC=Allophycocyanin) for 1 hour at RT. Test compounds, at various concentrations, were preincubated 10 min in human plasma (anticoagulated with a thrombin inhibitor). Then, human plasma was added to the polymorphonuclear cells to 50% of final assay volume with polymorphonuclear cells at 4×10⁶ cells/ml. After incubation for 10 minutes at 37° C., the polymorphonuclear cells were activated for 5 min at 37° C. by addition of PGD₂ at 100 nM final concentration. Activation was stopped by addition of 0.5 ml paraformaldehyde (1%).

Immediately after fixation with paraformaldehyde, the samples were analyzed by FACSCanto flow cytometer (BD Biosciences) and target cells were identified by their forward-scatter (FSC) and side-scatter (SSC) characteristics. Eosinophils were identified by the anti-CD49d-APC signal and their characteristic side-scatter (SSC) profile. Shape change responses, indicative of eosinophil activation, were quantified as the percent of cells with an increased forward-scatter.

Antagonistic activities of selected compounds are displayed in the following Table:

IC₅₀ Example Name [nM] 1 (±)-(3-{5-Fluoro-2-[trans-2-(4-fluoro-phenyl)- 8 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 5 (±)-(3-{5-Fluoro-2-[trans-2-(2-fluoro-phenyl)- 12 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 21 8-(5-Carboxymethyl-2-trifluoromethoxy-phenyl)-5-fluoro-3,4- 64 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 22 8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro- 38 1H-isoquinoline-2-carboxylic acid benzyl ester 28 {4-Chloro-3-[5-fluoro-2-((1R,2R)-2-phenyl- 42 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 29 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 20 tetrahydro-isoquinolin-8-yl]-4-methanesulfonyl-phenyl}-acetic acid 31 8-(5-Carboxymethyl-2-methoxy-phenyl)-5,6-difluoro-3,4-dihydro- 436 1H-isoquinoline-2-carboxylic acid benzyl ester 32 8-(5-Carboxymethyl-2-methoxy-phenyl)-6-fluoro-3,4-dihydro-1H- 356 isoquinoline-2-carboxylic acid benzyl ester 34 {3-[6-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 25 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 36 (±)-{3-[9-Fluoro-3-(trans-2-phenyl-cyclopropanecarbonyl)-2,3,4,5- >1000 tetrahydro-1H-benzo[d]azepin-6-yl]-4-methoxy-phenyl}-acetic acid 37 (±)-{3-[7-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-2,3- 289 dihydro-1H-isoindol-4-yl]-4-methoxy-phenyl}-acetic acid 39 8-(5-Carboxymethyl-2-methoxy-phenyl)-5,7-difluoro-3,4-dihydro- 404 1H-isoquinoline-2-carboxylic acid benzyl ester 42 (3-{5-Fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4- 118 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 45 (3-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 64 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 48 (±)-(3-{5-Fluoro-2-[trans-2-(3-fluoro-phenyl)- 42 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 54 {3-[5-Fluoro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro- 184 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 58 (3-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro- 122 isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 59 {3-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-5-fluoro-1,2,3,4- 182 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 60 (±)-{3-[5-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 13 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 61 (3-{5-Fluoro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 52 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 62 (3-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 106 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 65 (3-{5-Fluoro-2-[(1R,2R)-2-(3-fluoro-phenyl)- 10 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 69 (3-{5-Chloro-2-[(1R,2R)-2-(3-fluoro-phenyl)- 78 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4- methoxy-phenyl)-acetic acid 71 {3-[5-Chloro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 22 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 80 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 4.7 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 83 (±)-{4-Methoxy-3-[2-(trans-2-phenyl-cyclopropanecarbonyl)-5- >1000 trifluoromethyl-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 84 {3-[5,6-Difluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)- 5 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 106 {3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 37 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 108 {3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 92 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 125 (3-{5-Fluoro-2-[3-(3-methyl-indazol-1-yl)-propionyl]-1,2,3,4- 113 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 132 {3-[5-Fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro- >1000 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 138 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 908 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 139 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 97 isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester 146 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 266 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 147 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 622 isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester 154 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-chloro-3,4-dihydro-1H- 307 isoquinoline-2-carboxylic acid benzyl ester 157 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 153 isoquinoline-2-carboxylic acid benzyl ester 162 8-(5-Carboxymethoxy-2-trifluoromethoxy-phenyl)-5-fluoro-3,4- 170 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 163 8-(5-Carboxymethoxy-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro- 141 1H-isoquinoline-2-carboxylic acid benzyl ester 166 8-(4-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 117 isoquinoline-2-carboxylic acid benzyl ester 168 8-(7-Carboxymethyl-2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-fluoro- 133 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 169 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-cyano-3,4-dihydro-1H- 146 isoquinoline-2-carboxylic acid benzyl ester 177 8-(5-Carboxymethoxy-2-methoxy-phenyl)-5-fluoro-3,4-dihydro- 539 1H-isoquinoline-2-carboxylic acid benzyl ester 182 {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 34 tetrahydro-isoquinolin-8-yl]-4-methoxy-phenoxy}-acetic acid 183 (4-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 194 tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 185 (4-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 97 isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 187 {4-[5-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8- 91 yl]-3-methoxy-phenyl}-acetic acid 188 {4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 8 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 189 {4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 62 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 193 (4-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro- 94 isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 194 {4-[5-Fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin- 188 8-yl]-3-methoxy-phenyl}-acetic acid 195 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 21 isoquinoline-2-carboxylic acid benzyl ester 196 8-(5-Carboxymethyl-2-cyclopropylmethoxy-phenyl)-5-fluoro-3,4- 44 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 197 8-(5-Carboxymethyl-2-propoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 24 isoquinoline-2-carboxylic acid benzyl ester 198 8-(5-Carboxymethyl-2-isobutoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 72 isoquinoline-2-carboxylic acid benzyl ester 199 8-[5-Carboxymethyl-2-(2-methoxy-ethoxy)-phenyl]-5-fluoro-3,4- 19 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 200 {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 50 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid (enantiomer 1) 201 {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 31 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid (enantiomer 2) 203 {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 12 isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 1) 204 {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 30 isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 205 {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 17 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 1) 206 {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 14 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 207 {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 15 tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid (enantiomer 1) 208 {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 42 tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid (enantiomer 2) 209 {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4- 13 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 1) 210 {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4- 11 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 211 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-butyryl]-1,2,3,4- 7 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid (enantiomer 1) 214 {4-Ethoxy-3-[5-fluoro-2-(2-methyl-3-phenyl-propionyl)-1,2,3,4- 11 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid (enantiomer 2) 217 8-(4-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro- 46 1H-isoquinoline-2-carboxylic acid benzyl ester 221 {4-Ethoxy-3-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 34 isoquinolin-8-yl]-phenyl}-acetic acid 222 (4-Ethoxy-3-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4- 21 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 223 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]- 19 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 224 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 10 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 225 {4-Ethoxy-3-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4- 37 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 226 (±)-{3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 43 isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 227 (±)-{3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 38 tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 228 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4- 8 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 229 (±)-{3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4- 15 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 230 (3-Ethoxy-4-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4- 19 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 234 {3-Ethoxy-4-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 47 isoquinolin-8-yl]-phenyl}-acetic acid 235 (±)-{4-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4- 20 tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid 236 (±)-{4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 12 isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid 237 (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]- 9 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 238 {3-Ethoxy-4-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4- 15 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 240 (±)-(3-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4- 31 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 243 (±)-(3-{5-Fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4- 92 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 252 (3-{5-Fluoro-2-[3-(3-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4- 258 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 253 (±)-{3-[2-(2-{[(4-Chloro-phenyl)-phenyl-methyl]-methyl-amino}- 399 acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy- phenyl}-acetic acid 257 (±)-{3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro- 35 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 258 (3-{5-Fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4- 101 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 260 (±)-{3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-2-yl-acetyl)- 56 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 261 (±)-{3-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro- 86 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 262 (±)-{3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 66 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 263 (±)-{3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-1-yl-acetyl)- 64 1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 265 (±)-{3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro- 98 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 271 (±)-{3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro- 91 isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid 275 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(3-fluoro-phenyl)-cyclopropyl]- 76 acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid 277 [4-Ethoxy-3-(5-fluoro-2-{2-[1-(4-fluoro-phenyl)-cyclopropyl]- 21 acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid 278 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-butyryl]-1,2,3,4- 19 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 279 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro-phenyl)-butyryl]-1,2,3,4- 45 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 310 (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-propionyl]-1,2,3,4- 7 tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 321 (3-Ethoxy-4-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]- 20 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 328 (±)-(4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]- 15 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 329 (4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]- 21 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 330 (±)-{4-Ethoxy-3-[5-fluoro-2-(trans-2-pyridin-2-yl- 15 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]- phenyl}-acetic acid 332 (±)-{3-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 15 isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid 335 (±)-(4-Ethoxy-3-{5-fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]- 26 1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid 344 (±)-{3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4- 51 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 345 (±)-{4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4- 31 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 348 {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4- 16 tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 350 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-5,6,7,8-tetrahydro-quinolin-8-yl- 9 acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 351 (±)-{4-Ethoxy-3-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)- 26 1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 352 (±)-{3-Ethoxy-4-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)- 103 1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid 358 (4-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4- 11 tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid 359 (±)-{4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 28 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 360 (±)-{4-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro- 30 isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid 363 (3-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4- 20 tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid 365 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 32 isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 366 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 65 isoquinoline-2-carboxylic acid 3-fluoro-5-methyl-pyridin-2- ylmethyl ester 368 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 46 isoquinoline-2-carboxylic acid (S)-1-phenyl-ethyl ester 369 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 266 isoquinoline-2-carboxylic acid cyclopentylmethyl ester 370 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 76 isoquinoline-2-carboxylic acid 3-methyl-butyl ester 371 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 23 isoquinoline-2-carboxylic acid 6-methyl-pyridin-2-ylmethyl ester 372 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 149 isoquinoline-2-carboxylic acid cyclopropylmethyl ester 373 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 42 isoquinoline-2-carboxylic acid phenethyl ester 374 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 28 isoquinoline-2-carboxylic acid (R)-2-phenyl-propyl ester 376 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 59 isoquinoline-2-carboxylic acid butyl ester 377 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 123 isoquinoline-2-carboxylic acid isobutyl ester 389 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 122 isoquinoline-2-carboxylic acid (S)-1-phenyl-ethyl ester 394 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 12 isoquinoline-2-carboxylic acid pyridin-2-ylmethyl ester 396 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 18 isoquinoline-2-carboxylic acid cyclohexylmethyl ester 397 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 15 isoquinoline-2-carboxylic acid cyclohexylmethyl ester 398 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 13 isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester 399 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 29 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 400 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 21 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 401 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 26 isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester 402 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 20 isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester 403 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 15 isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester 404 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 10 isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester 405 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 20 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 406 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 10 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 407 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 9 isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester 408 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 8 isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester 409 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 5 isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester 410 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H- 13 isoquinoline-2-carboxylic acid benzyl ester 411 8-[4-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro- 13 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 412 8-(5-Carboxymethyl-2-difluoromethoxy-phenyl)-5-fluoro-3,4- 47 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 413 8-[5-Carboxymethyl-2-(2,2-difluoro-ethoxy)-phenyl]-5-fluoro-3,4- 44 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 419 8-(2-tert-Butoxy-5-carboxymethyl-phenyl)-5-fluoro-3,4-dihydro- 35 1H-isoquinoline-2-carboxylic acid benzyl ester 420 8-(5-Carboxymethyl-2-dimethylamino-phenyl)-5-fluoro-3,4- 17 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 421 8-[5-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro- 16 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 422 8-[5-Carboxymethyl-2-(2-fluoro-ethoxy)-phenyl]-5-fluoro-3,4- 8 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 431 8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-cyano-3,4-dihydro- 47 1H-isoquinoline-2-carboxylic acid benzyl ester 438 [3-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8- 14 yl)-4-ethoxy-phenyl]-acetic acid

Intracellular Calcium Mobilization Assay (FLIPR):

Cells (HEK-293), stably expressing the hCRTH2 receptor under the control of the cytomegalovirus promotor from a single insertion of the expression vector pcDNA5 (Invitrogen), are grown to confluency in DMEM (low glucose, Gibco) medium supplemented with 10% fetal calf serum (Bioconcept, Switzerland) under standard mammalian cell culture conditions (37° C. in a humidified atmosphere of 5% CO₂). Cells are detached from culture dishes using a dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, and collected by centrifugation at 200 g at r.t. for 5 min in assay buffer (equal parts of Hank's BSS (HBSS, Bioconcept) and DMEM (low glucose, without phenol red, Gibco)). After incubation for 45 min (37° C. and 5% CO₂) in the presence of 1 μM Fluo-4 and 0.04% Pluronic F-127 (both Molecular Probes), and 20 mM HEPES (Gibco) in assay buffer, the cells are washed with and resuspended in assay buffer, then seeded onto 384-well FLIPR assay plates (Greiner) at 50,000 cells in 66 μl per well, and sedimented by centrifugation.

Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in assay buffer to concentrations required for inhibition dose response curves. Prostaglandin D₂ (Biomol, Plymouth Meeting, Pa.) is used as an agonist.

A FLIPR Tetra instrument (Molecular Devices) is operated according to the manufacturer's standard instructions, adding 4 μl of test compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. 10 μl of 80 nM prostaglandin D₂ (Biomol, Plymouth Meeting, Pa.) in assay buffer, supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%, Sigma), is then added to obtain a final concentration of 10 nM and 0.1%, respectively. Changes in fluorescence are monitored before and after the addition of test compounds at λ_(ex)=488 nm and λ_(em)=540 nm. Emission peak values above base level after prostaglandin D₂ addition are exported after base line subtraction. Values are normalized to high-level control (no test compound added) after subtraction of base line value (no prostaglandin D₂ added). The program XLIfit 3.0 (IDBS) is used to fit the data to a single site dose response curve of the equation (A+((B−A)/(1+((C/x)̂D)))) and to calculate the IC₅₀ values.

All compounds tested in the intracellular calcium mobilization assay have shown antagonistic activity. 

1. A compound of formula (I):

wherein R¹ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)alkylsulfonyl, halogen or cyano; R² represents hydrogen or halogen; one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkyl, carboxy-cyclopropyl or carboxy-(C₁-C₃)alkoxy and the other two represent independently of each other hydrogen, (C₁-C₄)alkoxy or halogen; R⁶ represents hydrogen, (C₁-C₄)alkoxy or halogen; R⁷ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₃-C₆)cycloalkyl-methoxy, (C₃-C₆)cycloalkyloxy, methoxy-ethoxy, di-[(C₁-C₂)alkyl]-amino, (C₁-C₄)fluoroalkyl, (C₁-C₄)fluoroalkoxy, halogen or (C₁-C₄)alkylsulfonyl; or R⁶ and R⁷ together represent methylendioxy or ethylendioxy; R⁸ represents (C₂-C₅)alkyl; (C₁-C₅)alkyl which is mono- or di-substituted wherein the substituents are independently selected from hydroxy, (C₁-C₄)alkoxy, oxo, —NR⁹R¹⁰, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryloxy, optionally substituted heteroaryloxy or optionally substituted aryl-(C₁-C₂)alkoxy; (C₃-C₅)alkenyl; (C₂-C₃)alkenyl which is mono-substituted with optionally substituted aryl or optionally substituted heteroaryl; (C₃-C₅)alkynyl; (C₃-C₆)cycloalkyl which is unsubstituted, mono-, di-, tri- or tetra-substituted with methyl; mono-substituted with oxo; mono-substituted with optionally substituted aryl; or mono-substituted with optionally substituted heteroaryl; or heterocyclyl which is optionally mono-substituted with oxo; R⁹ represents (C₁-C₄)alkyl; R¹⁰ represents optionally substituted diphenylmethyl; n represents 1 or 2; m represents 1 or 2; and Z represents —NH—, —O— or a bond; or a salt thereof.
 2. The compound according to claim 1, wherein R¹ represents hydrogen or halogen; R² represents hydrogen or halogen; one of R³, R⁴ and R⁵ represents carboxy-(C₁-C₃)alkyl or carboxy-(C₁-C₃)alkoxy and the other two represent hydrogen; R⁶ represents hydrogen, methoxy or halogen; R⁷ represents hydrogen, (C₁-C₄)alkoxy, trifluoromethyl, trifluoromethoxy, halogen or methylsulfonyl; R⁸ represents (C₁-C₄)alkyl which is mono-substituted with optionally substituted aryl, optionally substituted heteroaryl or optionally substituted aryl-(C₁-C₂)alkoxy; or cyclopropyl which is mono-substituted with optionally substituted aryl; n represents 1 or 2; m represents 1 or 2; and Z represents —NH—, —O— or a bond; or a salt thereof.
 3. The compound according to claim 1, wherein R¹ represents fluoro; R², R³, R⁴ and R⁶ represent hydrogen; R⁵ represents carboxy-methyl or 1-carboxy-ethyl; R⁷ represents methoxy, ethoxy, isopropoxy or 2,2,2-trifluoroethoxy; R⁸ represents a methyl, ethyl or n-propyl group, which groups are independently mono-substituted with phenyl, wherein the phenyl is unsubstituted, mono-substituted with fluoro, chloro, methyl or methoxy, di-substituted with fluoro, or di-substituted with fluoro and chloro; or pyridin-2-yl, wherein the pyridin-2-yl is unsubstituted, mono-substituted with methyl, or di-substituted with methyl and fluoro; n represents 1; m represents 2; and Z represents —O— or a bond; or a salt thereof.
 4. The compound according to claim 1, wherein R¹ represents fluoro, chloro or cyano; R², R³, R⁵ and R⁶ represent hydrogen; R⁴ represents carboxy-methyl or 1-carboxy-ethyl; R⁷ represents methoxy, ethoxy, n-propoxy, iso-propoxy, iso-butoxy, tert-butoxy, cyclopropyl-methoxy, methoxy-ethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy; R⁸ represents a methyl, ethyl or n-propyl group, which groups are independently mono-substituted with phenyl, wherein the phenyl is unsubstituted, mono-substituted with fluoro, chloro or methoxy, di-substituted with fluoro, or di-substituted with fluoro and chloro; or pyridin-2-yl, wherein the pyridin-2-yl is unsubstituted, mono-substituted with methyl, or di-substituted with methyl and fluoro; n represents 1; m represents 2; and Z represents —O— or a bond; or a salt thereof.
 5. The compound according to claim 1, wherein R¹ represents hydrogen, fluoro or chloro; or a salt thereof.
 6. The compound according to claim 1, wherein one of R³, R⁴ and R⁵ represents carboxy-methyl, 1-carboxy-ethyl or carboxy-methoxy; or a salt thereof.
 7. The compound according to claim 1, wherein R⁷ represents (C₁-C₄)alkoxy or trifluoromethoxy; or a salt thereof.
 8. The compound according to claim 1, wherein Z represents —O— and R⁸ represents (C₁-C₄)alkyl which is mono-substituted with optionally substituted aryl or optionally substituted heteroaryl; or Z represents a bond and R⁸ represents (C₁-C₄)alkyl which is mono-substituted with optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy or optionally substituted aryl-methoxy; or cyclopropyl which is mono-substituted with optionally substituted aryl; or a salt thereof.
 9. The compound according to claim 1, wherein Z represents a bond; or a salt thereof.
 10. The compound according to claim 1, wherein the compound is: (3-{5-Fluoro-2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[trans-2-(4-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[trans-2-(2-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[trans-2-(3-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[trans-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; 8-(5-Carboxymethyl-2-methyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-trifluoromethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-4-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-4-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-4-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-5-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-5-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 6-(5-Carboxymethyl-2-methoxy-phenyl)-9-fluoro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester; 4-(5-Carboxymethyl-2-methoxy-phenyl)-7-fluoro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methanesulfonyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-trifluoromethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-trifluoromethoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; {4-Chloro-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methanesulfonyl-phenyl}-acetic acid; 8-(2-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-7-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {3-[6-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[7-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[9-Fluoro-3-(trans-2-phenyl-cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yl]-4-methoxy-phenyl}-acetic acid; {3-[7-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-2,3-dihydro-1H-isoindol-4-yl]-4-methoxy-phenyl}-acetic acid; {3-[5,7-Difluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-3-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (3-{5-Fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(4-fluoro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-(2-Ethoxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(2-tert-Butoxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[trans-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-pyridin-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; [3-(2-Cyclopropanecarbonyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid; {3-[2-(3-3,4-Dihydro-2H-quinolin-1-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(2,2-Dimethyl-cyclopropanecarbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[3-(3-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[(1R,2R)-2-(4-Chloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[(1R,2R)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Chloro-2-[(1R,2R)-2-(4-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Chloro-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Chloro-2-[(1R,2R)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Chloro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Chloro-2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Chloro-2-[2-(2-chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Chloro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Chloro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Chloro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Chloro-2-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Chloro-2-(3-2,3-dihydro-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Chloro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; [3-(2-Cyclopropanecarbonyl-5-trifluoromethyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid; {4-Methoxy-3-[2-(trans-2-phenyl-cyclopropanecarbonyl)-5-trifluoromethyl-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-[5,6-Difluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[(E)-(3-phenyl-acryloyl)]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[(E)-3-(6-methoxy-pyridin-3-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[(E)-3-(2,4-Dimethyl-thiazol-5-yl)-acryloyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-((E)-3-Benzothiazol-2-yl-acryloyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-((E)-3-pyridin-3-yl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{2-[(E)-3-(2,5-Dimethyl-2H-pyrazol-3-yl)-acryloyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(3-pyrimidin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(pyridin-3-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[trans-2-(4-methoxy-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[3-(4-Chloro-phenyl)-3-phenyl-propionyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[trans-2-(2,4-Dichloro-phenyl)-cyclopropanecarbonyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[8-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid; {3-[8-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid; {3-[8-Fluoro-2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid; {3-[8-Fluoro-2-(3-phenoxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid; (3-{2-[2-(2-Chloro-benzyloxy)-acetyl]-8-fluoro-1,2,3,4-tetrahydro-isoquinolin-5-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-(3-3,4-Dihydro-2H-quinolin-1-yl-propionyl)-8-fluoro-1,2,3,4-tetrahydro-isoquinolin-5-yl]-4-methoxy-phenyl}-acetic acid; (3-{8-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-5-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-methyl-3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(indane-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-indan-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(indane-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(Chroman-3-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(4-oxo-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(Chroman-2-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(Bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(4-oxo-4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(1-methyl-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; 2-{3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-propionic acid; {3-[2-(2-Benzo[d]isoxazol-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-oxo-indane-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-1H-indazol-3-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[3-(3-methyl-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-(2-Cyclohexyl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(1-hydroxy-cyclohexyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-(3,3-Dimethyl-butyryl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; [3-(5-Fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid; {3-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; [3-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid; [3-(5-Fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester; 8-[5-(1-Carboxy-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ethyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid isobutyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid isopropyl ester; 8-(3-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-4-ylmethyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-5-ylmethyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 5-(5-Carboxymethyl-2-methoxy-phenyl)-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-trifluoromethoxy-phenoxy}-acetic acid; {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenoxy}-acetic acid; 8-(5-Carboxymethoxy-2-trifluoromethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethoxy-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-2-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(6-Carboxymethyl-benzo[1,3]dioxol-4-yl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(7-Carboxymethyl-2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[5-(1-Carboxy-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[2-(3-Carboxy-propoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethoxy-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethoxy-2-chloro-phenyl)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethoxy-2-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenoxy}-acetic acid; (4-{5-Fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid; {4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; (4-{5-Fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid; (4-{5-Fluoro-2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid; {4-[5-Fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; {4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; {4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; (4-{5-Fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid; {4-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; (4-{5-Fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid; (4-{2-[2-(2-Chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid; {4-[5-Fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-cyclopropylmethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-propoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-isobutoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; or 8-[5-Carboxymethyl-2-(2-methoxy-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; or a salt thereof.
 11. The compound according to claim, wherein the compound is: {4-[2-((S)-2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; {4-[2-((R)-2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; 8-[4-(1-Carboxy-ethoxy)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {4-Ethoxy-3-[5-fluoro-2-((S)-3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((R)-3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-((S)-2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-((R)-2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-[2-(2-[(S)-2,3-Dihydro-benzofuran-3-yl]-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid; {3-[2-(2-[(R)-2,3-Dihydro-benzofuran-3-yl]-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((S)-2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((R)-2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[(S)-3-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[(R)-3-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((S)-2-methyl-3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((R)-2-methyl-3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; 8-(5-Carboxymethyl-2-propyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-2-isopropyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethyl-2,6-dimethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {4-Ethoxy-3-[5-fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid; {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {3-Ethoxy-4-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid; {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[2-(6-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-(3-Cyclopropyl-butyryl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(8-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(2-5,6,7,8-tetrahydro-isoquinolin-8-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[3-(6-methoxy-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[2-(1-phenyl-cyclobutyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; [3-(5-Fluoro-2-{2-[1-(4-fluoro-phenyl)-cyclobutyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid; (3-{5-Fluoro-2-[3-(3-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[2-(2-{[(4-Chloro-phenyl)-phenyl-methyl]-methyl-amino}-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(2-Cyclopropyl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-((R)-2-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-hydroxy-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[2-(1-phenyl-cyclopropyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[2-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-1,2,3,4-tetrahydro-naphthalen-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(4-methyl-3-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-pyridin-3-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-pyridin-4-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-((R)-1,2,3,4-tetrahydro-naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(Chroman-4-carbonyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(isochroman-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(isochroman-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; [4-Ethoxy-3-(5-fluoro-2-{2-[1-(3-fluoro-phenyl)-cyclopropyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid; [4-Ethoxy-3-(5-fluoro-2-{2-[1-(2-fluoro-phenyl)-cyclopropyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid; [4-Ethoxy-3-(5-fluoro-2-{2-[1-(4-fluoro-phenyl)-cyclopropyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(3-pyrazin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(2-methoxy-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(3-thiazol-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (3-{2-[2-(2,2-Dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-ethoxy-phenyl)-acetic acid; [4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [4-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [4-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; {3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-isopropoxy-phenyl)-acetic acid; (3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-isopropoxy-phenyl)-acetic acid; {3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; {3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-isopropoxy-phenyl}-acetic acid; [3-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-{5-Fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-[5-Fluoro-2-(2-isochroman-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-[5-Fluoro-2-(2-isochroman-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; [3-[2-(2-2,3-Dihydro-benzofuran-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(3-methoxy-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(4-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(3-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[3-(3-methoxy-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[3-(4-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[3-(3-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {3-[2-(3-Cyclopropyl-3-pyridin-2-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid; {4-[2-(3-Cyclopropyl-3-pyridin-2-yl-propionyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(trans-2-pyridin-2-yl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-ethoxy-phenyl)-acetic acid; {4-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(trans-2-pyridin-2-yl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (3-{2-[2-(2,2-Dimethyl-chroman-4-yl)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-ethoxy-phenyl)-acetic acid; {3-[2-(2-Chroman-3-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[2-(1-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[2-(7-fluoro-chroman-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {4-Ethoxy-3-[5-fluoro-2-((E)-3-pyridin-2-yl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-3-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {3-Ethoxy-4-[5-fluoro-2-((E)-3-pyridin-2-yl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-4-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(2-pyridin-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; (4-Ethoxy-3-{5-fluoro-2-[(E)-3-(1-methyl-1H-pyrazol-4-yl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(2-pyridin-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-[5-Fluoro-2-(2-methyl-3-pyridin-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-[5-Fluoro-2-(3-pyridin-2-yl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid; [4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(2-5,6,7,8-tetrahydro-quinolin-8-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(2-methyl-3-pyridin-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid; {4-[5-Fluoro-2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid; {4-[5-Fluoro-2-((S)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid; {4-[5-Fluoro-2-((R)-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid; {4-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-isopropoxy-phenyl}-acetic acid; (4-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-3-methoxy-phenyl)-acetic acid; {4-[2-(2-Chroman-4-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; {4-[5-Fluoro-2-(2-indan-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-methoxy-phenyl}-acetic acid; {3-[5-Fluoro-2-(trans-2-pyridin-2-yl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; {3-[2-(2-1,3-Dihydro-isobenzofuran-1-yl-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-acetic acid; (3-{5-Fluoro-2-[3-(4-fluoro-phenyl)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-4-methoxy-phenyl)-acetic acid; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (R)-1-phenyl-ethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-5-methyl-pyridin-2-ylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (S)-1-phenyl-ethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclopentylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-butyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 6-methyl-pyridin-2-ylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclopropylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (R)-2-phenyl-propyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-but-2-enyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid butyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid isobutyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methoxy-ethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-but-3-enyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-butyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid but-3-ynyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-hydroxy-3-methyl-butyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methoxy-3-methyl-butyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tetrahydro-furan-2-ylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (R)-1-phenyl-ethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-5-methyl-pyridin-2-ylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (S)-1-phenyl-ethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 6-methyl-pyridin-2-ylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclopropylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclopentylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-butyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyridin-2-ylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyridin-2-ylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclohexylmethyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclohexylmethyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester; 8-(5-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester; 8-(4-Carboxymethyl-2-ethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[4-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-difluoromethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[5-Carboxymethyl-2-(2,2-difluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[5-(1-Carboxy-ethoxy)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[5-(1-Carboxy-propoxy)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(2-Carboxymethyl-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(2-Carboxymethoxy-6-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(2-Carboxymethyl-6-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(2-tert-Butoxy-5-carboxymethyl-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-dimethylamino-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[5-Carboxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[5-Carboxymethyl-2-(2-fluoro-ethoxy)-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(3-Carboxymethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(4-Carboxymethoxy-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-[4-(1-Carboxy-ethyl)-2-ethoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; [3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid; {4-(2-Fluoro-ethoxy)-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-tert-Butoxy-3-[5-fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; 1-{3-[5-Fluoro-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-methoxy-phenyl}-cyclopropanecarboxylic acid; 8-(5-Carboxymethyl-2-cyclopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 8-(5-Carboxymethyl-2-isopropoxy-phenyl)-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {4-Ethoxy-3-[5-fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; [4-Ethoxy-3-(5-fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid; {3-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-4-ethoxy-phenyl}-acetic acid; {4-Ethoxy-3-[5-fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; [3-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-ethoxy-phenyl]-acetic acid; [4-Ethoxy-3-(5-fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; [3-Ethoxy-4-(5-fluoro-2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid; {4-[2-(2-Chloro-benzylcarbamoyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl]-3-ethoxy-phenyl}-acetic acid; {3-Ethoxy-4-[5-fluoro-2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-phenyl}-acetic acid; [4-(2-Benzylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-3-ethoxy-phenyl]-acetic acid; [3-Ethoxy-4-(5-fluoro-2-propylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid; (3-Ethoxy-4-{5-fluoro-2-[(pyridin-2-ylmethyl)-carbamoyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; or (4-Ethoxy-3-{5-fluoro-2-[(pyridin-2-ylmethyl)-carbamoyl]-1,2,3,4-tetrahydro-isoquinolin-8-yl}-phenyl)-acetic acid; or a salt of such a compound.
 12. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 13. A medicament comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof.
 14. A method of treating or preventing a disease or disorder comprising administering an amount of the compound according to claim 1 to a subject in need thereof, wherein the disease is chronic and acute allergic/immune diseases/disorders eosinophil-related diseases; or basophil-related diseases.
 15. A method of treating or preventing a disease or disorder comprising administering an amount of the compound according to claim 12 to a subject in need thereof, wherein the disease is chronic and acute allergic/immune diseases/disorders, eosinophil-related diseases; or basophil-related diseases.
 16. The method according to claim 14, wherein the chronic and acute allergic/immune diseases/disorders are asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease or rheumatoid arthritis.
 17. The method according to claim 14, wherein the eosinophil-related diseases are small vessel vasculitides, Wegener's granulomatosis, microscopic polyangiitis and organ-specific subsets, hypereosinophilic syndromes, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia or DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
 18. The method according to claim 17, wherein the small vessel vasculitides is Churg-Strauss syndrome.
 19. The method according to claim 17, wherein hypereosinophilic syndromes is eosinophilic pneumonia.
 20. The method according to claim 14, wherein the basophil-related diseases are basophilic leukemia or basophilic leukocytosis 